Cancer Research and Treatment

Original Articles

Clinical Impact of TP53 Mutations in Patients with Head and Neck Cancer Who Were Treated with Targeted Therapies or Immunotherapy: Eun Joo Kang, Shinwon Hwang, Yun-Gyoo Lee, Jong-Kwon Choi, Seong Hoon Shin, Yoon Hee Choi, Keun-Wook Lee, Hyun Woo Lee, Min Kyoung Kim, Seung Taek Lim, Hwan Jung Yun, Sang-Gon Park, Sangwoo Kim, Sung-Bae Kim, Hye Ryun Kim; Received August 28, 2024 Accepted December 21, 2024 Published online December 23, 2024; DOI: https://doi.org/10.4143/crt.2024.836 [Accepted]

Abstract PDF: Purpose
TP53 mutations are common in head and neck squamous cell carcinoma (HNSCC). We evaluated their clinical impact in patients treated with targeted agents or immunotherapy in the KCSG HN15-16 TRIUMPH trial.
Materials and Methods
We analyzed clinical characteristics and outcomes of patients with TP53 mutations in the TRIUMPH trial, a multicenter, biomarker-driven umbrella trial in Korea. Patients were assigned to treatment groups based on genomic profiles: Group 1, alpelisib; Group 2, poziotinib; Group 3, nintedanib; and Group 4, abemaciclib. If there was no identifiable target, the patients were allocated to Group 5 (durvalumab ± tremelimumab).
Results
TP53 mutations were detected in 116/179 patients (64.8%), more frequently in HPV-negative and non-oropharyngeal cancers. Patients with TP53 mutations exhibited shorter progression-free survival (PFS) than TP53 wild-type in all the patients (1.7 vs. 3.8 months, p=0.002) and in those who received targeted treatments (2.5 vs. 7.3 months, p=0.009). Furthermore, TP53 mutations were strongly associated with poor overall survival than TP53 wild-type in all the patients (11.1 vs. 28.8 months, p=0.005) and in Group 5 (8.1 vs. 33.0 months, p=0.001).
Conclusion
TP53 mutations were associated with aggressive clinical characteristics and poor survival, particularly in HNSCC patients treated with immunotherapy.

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Prognostic Value of TP53 Mutation for Transcatheter Arterial Chemoembolization Failure/Refractoriness in HBV-Related Advanced Hepatocellular Carcinoma: Miao Xue, Yanqin Wu, Wenzhe Fan, Jian Guo, Jialiang Wei, Hongyu Wang, Jizhou Tan, Yu Wang, Wang Yao, Yue Zhao, Jiaping Li; Cancer Res Treat. 2020;52(3):925-937. Published online March 30, 2020; DOI: https://doi.org/10.4143/crt.2019.533

Purpose
This study aimed to investigate the clinicopathologic features and mutational landscape of patients with hepatitis B virus (HBV)–related advanced hepatocellular carcinomas (HCC) undergoing transcatheter arterial chemoembolization (TACE).
Materials and Methods
From January 2017 to December 2018, 38 patients newly diagnosed with HBV-related advanced HCC were enrolled in the final analysis. Their pathological tissues and corresponding blood samples before TACE treatment were collected for whole-exome sequencing. Response to TACE was evaluated at 1-3 months after two consecutive use of TACE. Predictive factors were analyzed by univariate and multivariate analyses in a bivariate Logistic regression model. Enrichment of related pathways of all driver genes were acquired using the gene set enrichment analysis (GSEA).
Results
Among 38 patients, 23 (60.5%) exhibited TACE failure/refractoriness. Patients with TACE failure/refractoriness showed higher frequency of TP53 mutation than their counterparts (p=0.020). Univariate and multivariate analyses showed that only vascular invasion and TP53 mutation were significantly correlated with TACE failure/refractoriness in HBV-related advanced HCC. Of the 16 patients without vascular invasion, eight (50.0%) had TP53 mutations, and TP53 mutation was associated with TACE failure/refractoriness (p=0.041). Moreover, GSEA showed that mitogen-activated protein kinase and apoptosis pathways induced by TP53 mutation were possibly associated with TACE failure/refractoriness.
Conclusion
Our study suggested that TP53 mutation was independently related with TACE efficacy, which may work via mitogen-activated protein kinase and apoptosis pathways. These findings may provide evidence to help distinguish patients who will particularly benefit from TACE from those who require more personalized therapeutic regimens and rigorous surveillance in HBV-related advanced HCC.

Citations

Citations to this article as recorded by

Therapeutic efficacy and prognostic indicators in re-resection for recurrent hepatocellular carcinoma: Insights from a retrospective study
Qi Fan, Pengcheng Wei, Delin Ma, Qian Cheng, Jie Gao, Jiye Zhu, Zhao Li
Surgery Open Science.2025; 23: 16. CrossRef
TP53 Mutation Predicts Worse Survival and Earlier Local Progression in Patients with Hepatocellular Carcinoma Treated with Transarterial Embolization
Ken Zhao, Anita Karimi, Luke Kelly, Elena Petre, Brett Marinelli, Erica S. Alexander, Vlasios S. Sotirchos, Joseph P. Erinjeri, Anne Covey, Constantinos T. Sofocleous, James J. Harding, William Jarnagin, Carlie Sigel, Efsevia Vakiani, Etay Ziv, Hooman Yar
Current Oncology.2025; 32(1): 51. CrossRef
Clinical Therapy: HAIC Combined with Tyrosine Kinase Inhibitors and Programmed Cell Death Protein-1 Inhibitors versus HAIC Alone for Unresectable Hepatocellular Carcinoma
Baokun Liu, Lujun Shen, Wen Liu, Zhiyong Zhang, Jieqiong Lei, Zhengguo Li, Qinquan Tan, Hengfei Huang, Xingdong Wang, Weijun Fan
Journal of Hepatocellular Carcinoma.2024; Volume 11: 1557. CrossRef
Enhanced interactions within microenvironment accelerates dismal prognosis in HBV-related HCC after TACE
Libo Wang, Jiahui Cao, Zaoqu Liu, Shitao Wu, Yin Liu, Ruopeng Liang, Rongtao Zhu, Weijie Wang, Jian Li, Yuling Sun
Hepatology Communications.2024;[Epub] CrossRef
Development and validation of survival prediction models for patients with hepatocellular carcinoma treated with transcatheter arterial chemoembolization plus tyrosine kinase inhibitors
Kun Huang, Haikuan Liu, Yanqin Wu, Wenzhe Fan, Yue Zhao, Miao Xue, Yiyang Tang, Shi-Ting Feng, Jiaping Li
La radiologia medica.2024; 129(11): 1597. CrossRef
Identification of BRD7 by whole-exome sequencing as a predictor for intermediate-stage hepatocellular carcinoma in patients undergoing TACE
Kun Huang, Yanqin Wu, Wenzhe Fan, Yue Zhao, Miao Xue, Haikuan Liu, Yiyang Tang, Jiaping Li
Journal of Cancer Research and Clinical Oncology.2023; 149(13): 11247. CrossRef
Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score
Jia-Wei Zhong, Dan-Dan Nie, Ji-Lan Huang, Rong-Guang Luo, Qing-He Cheng, Qiao-Ting Du, Gui-Hai Guo, Liang-Liang Bai, Xue-Yun Guo, Yan Chen, Si-Hai Chen
Discover Oncology.2023;[Epub] CrossRef
Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems
Jose J.G. Marin, Marta R. Romero, Elisa Herraez, Maitane Asensio, Sara Ortiz-Rivero, Anabel Sanchez-Martin, Luca Fabris, Oscar Briz
Seminars in Liver Disease.2022; 42(01): 087. CrossRef
Non-Apoptotic Programmed Cell Death-Related Gene Signature Correlates With Stemness and Immune Status and Predicts the Responsiveness of Transarterial Chemoembolization in Hepatocellular Carcinoma
Guixiong Zhang, Wenzhe Fan, Hongyu Wang, Jie Wen, Jizhou Tan, Miao Xue, Jiaping Li
Frontiers in Cell and Developmental Biology.2022;[Epub] CrossRef
Plasma arginase-1 as a predictive marker for early transarterial chemoembolization refractoriness in unresectable hepatocellular carcinoma
Wei-Li Xia, Shi-Jun Xu, Yuan Guo, Xiao-Hui Zhao, Hong-Tao Hu, Yan Zhao, Quan-Jun Yao, Lin Zheng, Dong-Yang Zhang, Chen-Yang Guo, Wei-Jun Fan, Hai-Liang Li
Frontiers in Oncology.2022;[Epub] CrossRef
Useful genes for predicting the efficacy of transarterial chemoembolization in hepatocellular carcinoma
Yuan Guo, Hongtao Hu, Shijun Xu, Weili Xia, Hailiang Li
Journal of Cancer Research and Therapeutics.2022; 18(7): 1860. CrossRef
Development and Validation of a Predictive Model for Early Refractoriness of Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma
Tian-Cheng Wang, Tian-Zhi An, Jun-Xiang Li, Zi-Shu Zhang, Yu-Dong Xiao
Frontiers in Molecular Biosciences.2021;[Epub] CrossRef
Transcatheter arterial chemoembolization followed by surgical resection for hepatocellular carcinoma: a focus on its controversies and screening of patients most likely to benefit
Zhan-Qi Wei, Yue-Wei Zhang
Chinese Medical Journal.2021; 134(19): 2275. CrossRef
Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma
Young Chang, Soung Won Jeong, Jae Young Jang, Yong Jae Kim
International Journal of Molecular Sciences.2020; 21(21): 8165. CrossRef

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EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia: Dan-Min Xu, Yi-Lin Kong, Li Wang, Hua-Yuan Zhu, Jia-Zhu Wu, Yi Xia, Yue Li, Shu-Chao Qin, Lei Fan, Jian-Yong Li, Jin-Hua Liang, Wei Xu; Cancer Res Treat. 2020;52(2):492-504. Published online October 29, 2019; DOI: https://doi.org/10.4143/crt.2019.457

Abstract PDF Supplementary Material PubReader ePub

Purpose
The purpose of this study was to investigate the prognostic impact of Epstein-Barr virus (EBV)–microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene.
Materials and Methods
Quantitative reverse transcription–polymerase chain reaction and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL.
Results
p53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p < 0.001) which was also an independent prognostic marker for overall survival (p=0.028; hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLL patients after adjusted with International Prognostic Index for patients with CLL. We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3′- untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1- 1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines.
Conclusion
This study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

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Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer: Ah-Rong Nam, Mei Hua Jin, Ji Eun Park, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang; Cancer Res Treat. 2019;51(3):1167-1179. Published online December 3, 2018; DOI: https://doi.org/10.4143/crt.2018.526

Abstract PDF PubReader ePub

Purpose
The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor.
Materials and Methods
A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings.
Results
Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug.
Conclusion
In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

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Association between Mutation and Expression of TP53 as a Potential Prognostic Marker of Triple-Negative Breast Cancer: Ji-Yeon Kim, Kyunghee Park, Hae Hyun Jung, Eunjin Lee, Eun Yoon Cho, Kwang Hee Lee, Soo Youn Bae, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park; Cancer Res Treat. 2016;48(4):1338-1350. Published online February 18, 2016; DOI: https://doi.org/10.4143/crt.2015.430

Abstract PDF Supplementary Material PubReader ePub

Purpose
TP53, the most frequently mutated gene in breast cancer, is more frequently altered in HER2-enriched and basal-like breast cancer. However, no studies have clarified the role of TP53 status as a prognostic and predictive marker of triple-negative breast cancer (TNBC).
Materials and Methods
We performed p53 immunohistochemistry (IHC), nCounter mRNA expression assay, and DNA sequencing to determine the relationship between TP53 alteration and clinical outcomes of TNBC patients.
Results
Seventy-seven of 174 TNBC patients were found to harbor a TP53 mutation. Patients with missense mutations showed high protein expression in contrast to patients with deletion mutations (positivity of IHC: wild type vs. missense vs. deletion mutation, 53.6% vs. 89.8% vs. 25.0%, respectively; p < 0.001). TP53 mRNA expression was influenced by mutation status (mRNA expression [median]: wild type vs. missense vs. deletion mutation, 207.36± 132.73 vs. 339.61±143.21 vs. 99.53±99.57,respectively; p < 0.001). According to survival analysis, neither class of mutation nor protein or mRNA expression status had any impact on patient prognosis. In subgroup analysis, low mRNA expression was associated with poor prognosis in patientswith a TP53 missense mutation (5-year distantrecurrence-free survival [5Y DRFS]: low vs. high, 50.0% vs. 87.8%; p=0.009), while high mRNA expression with a TP53 deletion mutation indicated poor prognosis (5Y DRFS: low vs. high, 91.7% vs. 75.0%; p=0.316).
Conclusion
Association between TP53 mutation and expression indicates a potential prognostic marker of TNBC; hence both DNA sequencing and mRNA expression analysis may be required to predict the prognosis of TNBC patients.

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Ming Zhao, Erin W. Howard, Amanda B. Parris, Zhiying Guo, Qingxia Zhao, Xiaohe Yang
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Zongbi Yi, Fei Ma, Chunxiao Li, Rongrong Chen, Lifang Yuan, Xiaoying Sun, Xiuwen Guan, Lixi Li, Binliang Liu, Yanfang Guan, Haili Qian, Binghe Xu
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Oncotarget.2017; 8(17): 27997. CrossRef
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Oncotarget.2017; 8(63): 106270. CrossRef
Coexistent Loss of the Expressions of BRCA1 and p53 Predicts Poor Prognosis in Triple-Negative Breast Cancer
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The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer: Hae-Yun Jung, Hyun-Jung Joo, Jong Kuk Park, Yeul Hong Kim; Cancer Res Treat. 2012;44(4):251-261. Published online December 31, 2012; DOI: https://doi.org/10.4143/crt.2012.44.4.251

Abstract PDF PubReader ePub

PURPOSE
c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer.
MATERIALS AND METHODS
The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry.
RESULTS
SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein.
CONCLUSION
Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.

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Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents
Bassem H. Naguib, Heba A. Elsebaie, Mohamed S. Nafie, Samy Mohamady, Nader R. Albujuq, Aya Samir Ayed, Dina Nada, Ahmed F. Khalil, Salma M. Hefny, Haytham O. Tawfik, Moataz A. Shaldam
Bioorganic Chemistry.2024; 151: 107682. CrossRef
A Boolean Model of the Proliferative Role of the lncRNA XIST in Non-Small Cell Lung Cancer Cells
Shantanu Gupta, Daner A. Silveira, Ronaldo F. Hashimoto, Jose Carlos M. Mombach
Biology.2022; 11(4): 480. CrossRef
Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
Rapeepun Soonnarong, Ismail Dwi Putra, Nicharat Sriratanasak, Boonchoo Sritularak, Pithi Chanvorachote
Pharmaceuticals.2022; 15(5): 633. CrossRef
Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells
Ha-Na Oh, Ah-Won Kwak, Mee-Hyun Lee, Eunae Kim, Goo Yoon, Seung-Sik Cho, Kangdong Liu, Jung-Il Chae, Jung-Hyun Shim
Phytomedicine.2021; 80: 153355. CrossRef
Identification of four methylation-driven genes as candidate biomarkers for monitoring single-walled carbon nanotube-induced malignant transformation of the lung
Dongli Xie, Xiaogang Luo
Toxicology and Applied Pharmacology.2021; 412: 115391. CrossRef
Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer
Fatemeh Moosavi, Elisa Giovannetti, Godefridus J. Peters, Omidreza Firuzi
Critical Reviews in Oncology/Hematology.2021; 160: 103234. CrossRef
Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple‐negative breast cancer
Thomas D. Wright, Christopher Raybuck, Akshita Bhatt, Darlene Monlish, Suravi Chakrabarty, Katy Wendekier, Nathan Gartland, Mohit Gupta, Matthew E. Burow, Patrick T. Flaherty, Jane E. Cavanaugh
Journal of Cellular Biochemistry.2020; 121(2): 1156. CrossRef
The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells
Ibraheem M. Attafi, Saleh A. Bakheet, Hesham M. Korashy
Toxicology Mechanisms and Methods.2020; 30(3): 197. CrossRef
Folic acid-conjugated mesoporous silica particles as nanocarriers of natural prodrugs for cancer targeting and antioxidant action
Khaled AbouAitah, Anna Swiderska-Sroda, Ahmed A. Farghali, Jacek Wojnarowicz, Agata Stefanek, Stanislaw Gierlotka, Agnieszka Opalinska, Abdou K. Allayeh, Tomasz Ciach, Witold Lojkowski
Oncotarget.2018; 9(41): 26466. CrossRef
Genetic association analysis of the RTK/ERK pathway with aggressive prostate cancer highlights the potential role of CCND2 in disease progression
Yang Chen, Qin Zhang, Qiuyan Wang, Jie Li, Csilla Sipeky, Jihan Xia, Ping Gao, Yanling Hu, Haiying Zhang, Xiaobo Yang, Haitao Chen, Yonghua Jiang, Yuehong Yang, Ziting Yao, Yinchun Chen, Yong Gao, Aihua Tan, Ming Liao, Johanna Schleutker, Jianfeng Xu, Yin
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Regulation of theMEToncogene: molecular mechanisms
Jack Zhang, Andy Babic
Carcinogenesis.2016; 37(4): 345. CrossRef
The RTK/ERK pathway is associated with prostate cancer risk on the SNP level: A pooled analysis of 41 sets of data from case–control studies
Yang Chen, Tianyu Li, Xiaoqiang Yu, Jianfeng Xu, Jianling Li, Dexiang Luo, Zengnan Mo, Yanling Hu
Gene.2014; 534(2): 286. CrossRef
miR-210 over-expression enhances mesenchymal stem cell survival in an oxidative stress environment through antioxidation and c-Met pathway activation
JianFeng Xu, ZheYong Huang, Li Lin, MingQiang Fu, YanHua Gao, YunLi Shen, YunZeng Zou, AiJun Sun, JuYing Qian, JunBo Ge
Science China Life Sciences.2014; 57(10): 989. CrossRef
Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2
Mario Acunzo, Giulia Romano, Dario Palmieri, Alessandro Laganá, Michela Garofalo, Veronica Balatti, Alessandra Drusco, Mario Chiariello, Patrick Nana-Sinkam, Carlo M. Croce
Proceedings of the National Academy of Sciences.2013; 110(21): 8573. CrossRef
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Min Liu, Xiaohu Gu, Ke Zhang, Yi Ding, Xinbing Wei, Xiumei Zhang, Yunxue Zhao
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RTK/ERK Pathway under Natural Selection Associated with Prostate Cancer
Yang Chen, Xianxiang Xin, Jie Li, Jianfeng Xu, Xiaoxiang Yu, Tianyu Li, Zengnan Mo, Yanling Hu, Antimo Migliaccio
PLoS ONE.2013; 8(11): e78254. CrossRef

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Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression: Na-Hye Myong; Cancer Res Treat. 2010;42(2):95-100. Published online June 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.2.95

Abstract PDF PubReader ePub

Purpose

Functional inactivation of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene has been demonstrated as loss of MGMT protein and suggested that it plays an important role in primary human neoplasia, including lung cancer. It has also been reported to be associated with the G : C→A : T transition mutation in the p53 gene of lung cancer. The aims of this study were to investigate the role of MGMT expression loss and its prognostic significance in non-small cell lung carcinomas (NSCLCs), and its correlation with p53 overexpression as well as influence on patient survival.

Materials and Methods

112 surgically resected NSCLC specimens were reviewed by medical records for their clinicopathologic variables. Their tissue microarray blocks were immunostained with anti-human MGMT and p53 primary antibodies. Correlation between MGMT loss and the clinicopathologic prognostic factors, including p53 overexpression and the single or combined actions of MGMT loss and p53 overexpression on patient survival were statistically analyzed by SPSS15.0.

Results

Reduced or absent MGMT expression was found in 48 of 112 NSCLCs (43%), and significantly associated with nodal metastasis and squamous or undifferentiated cell types. Loss of MGMT expression was correlated with p53 overexpression in adenocarcinomas, but not in overall NSCLCs. Its solitary or combined actions with p53 overexpression did not have influence on patient survival.

Conclusion

Loss of MGMT expression is a relatively common event in NSCLCs and significantly associated with nodal metastasis and p53 overexpression, suggesting that it may play a major role in pulmonary carcinogenesis, and also in disease progression of NSCLCs.

Citations

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O 6 -Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer?
Birgitta I. Hiddinga, Patrick Pauwels, Annelies Janssens, Jan P. van Meerbeeck
Lung Cancer.2017; 107: 91. CrossRef
Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX
Carole Vitellius, Caroline Eymerit-Morin, Dominique Luet, Lionel Fizanne, Fanny Foubert, Sandrine Bertrais, Marie-Christine Rousselet, François-Xavier Caroli-Bosc
Clinical Drug Investigation.2017; 37(7): 669. CrossRef
Expression profiling of O6 methylguanine-DNA-methyl transferase in prolactinomas: a correlative study of promoter methylation and pathological features in 136 cases
Xiao-Bing Jiang, Bin Hu, Dong-Sheng He, Zhi-Gang Mao, Xin Wang, Bing-Bing Song, Yong-Hong Zhu, Hai-Jun Wang
BMC Cancer.2015;[Epub] CrossRef
Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours
Nicolas Bonello, James Sampson, John Burn, Ian J. Wilson, Gail McGrown, Geoff P. Margison, Mary Thorncroft, Philip Crossbie, Andrew C. Povey, Mauro Santibanez-Koref, Kevin Walters
Journal of Theoretical Biology.2013; 336: 87. CrossRef
Immunohistochemical Assessment of O6-Methylguanine-DNA Methyltransferase (MGMT) and Its Relationship with p53 Expression in Endometrial Cancers
Kyung Eun Lee
Journal of Cancer Prevention.2013; 18(4): 351. CrossRef

8,833 View
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p53 Prevents Immature Escaping from Cell Cycle G2 Checkpoint Arrest through Inhibiting cdk2-dependent NF-Y Phosphorylation: Un-Jung Yun, Heui-Dong Park, Deug Y Shin; Cancer Res Treat. 2006;38(4):224-228. Published online December 31, 2006; DOI: https://doi.org/10.4143/crt.2006.38.4.224

Abstract PDF PubReader ePub

Purpose

Recent studies have suggested that p53 regulates the G2 checkpoint in the cell cycle and this function is required for the maintenance of genomic integrity. In this study, we addressed a role of p53 in escaping from cell cycle G2 arrest following DNA damage.

Materials and Methods

Cell cycle checkpoint arrest in the human colon cancer cell line HCT116 and its derivatives carry p53 or p21 deletions, were examined by FACS analysis, immunoprecipitation, Western blot and IP-kinase assay.

Results

While the cells with functional p53 were arrested at both the G1 and G2 checkpoints, the p53-deficient cells failed to arrest at G1, but they were arrested at G2. However, the p53-deficient cells failed to sustain G2 checkpoint arrest and they entered mitosis earlier than did the p53-positive cells and so this resulted in extensive cell death. Cdc2 kinase becomes reactivated in p53-deficient cells in association with entry into mitosis, but not in the p53-positive cells. Upon DNA damage, the p21-deficient cells, like the p53-negative cells, not only failed to repress cdk2-dependent NF-Y phosphorylation, but they also failed to repress the expression of such cell cycle G2-regulatory genes as cdc2, cyclin B, RNR-R2 and cdc25C, which have all been previously reported as targets of NF-Y transcription factor.

Conclusions

p53 is essential to prevent immature escaping from cell cycle G2 checkpoint arrest through p21-mediated cdk2 inactivation, and this leads to inhibition of cdk2-dependent NF-Y phosphorylation and NF-Y dependent transcription of the cell cycle G2-rgulatory genes, including cdc2 and cyclin B.

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GRK2-mediated AKT activation controls cell cycle progression and G2 checkpoint in a p53-dependent manner
Verónica Rivas, Teresa González-Muñoz, Ángela Albitre, Vanesa Lafarga, Cristina Delgado-Arévalo, Federico Mayor, Petronila Penela
Cell Death Discovery.2024;[Epub] CrossRef
To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response
Qi Liu, Jinlan Gao, Chenyang Zhao, Yingying Guo, Shiquan Wang, Fei Shen, Xuesha Xing, Yang Luo
DNA Repair.2020; 85: 102702. CrossRef
The phosphorylatable Ser320 of NF‐YA is involved in DNA binding of the NF‐Y trimer
Andrea Bernardini, Mariangela Lorenzo, Marco Nardini, Roberto Mantovani, Nerina Gnesutta
The FASEB Journal.2019; 33(4): 4790. CrossRef
An LTR retrotransposon‐derived lnc RNA interacts with RNF 169 to promote homologous recombination
Bing Deng, Wenli Xu, Zelin Wang, Chang Liu, Penghui Lin, Bin Li, Qiaojuan Huang, Jianhua Yang, Hui Zhou, Lianghu Qu
EMBO reports.2019;[Epub] CrossRef
Repression of the F-box protein Skp2 is essential for actin damage-induced tetraploid G1 arrest
Yongsam Jo, Deug Y. Shin
BMB Reports.2017; 50(7): 379. CrossRef
The Role of AKT/mTOR Pathway in Stress Response to UV-Irradiation: Implication in Skin Carcinogenesis by Regulation of Apoptosis, Autophagy and Senescence
Elwira Strozyk, Dagmar Kulms
International Journal of Molecular Sciences.2013; 14(8): 15260. CrossRef
The NF-Y/p53 liaison: Well beyond repression
Carol Imbriano, Nerina Gnesutta, Roberto Mantovani
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2012; 1825(2): 131. CrossRef
Immortalization and malignant transformation of Eukaryotic cells
A. A. Stepanenko, V. M. Kavsan
Cytology and Genetics.2012; 46(2): 96. CrossRef

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Prognostic Significance of Immunohistochemical Expression of p53 Gene Product in Operable Breast Cancer: Hong Suk Song, Young Rok Do, Sun Hee Kang, Ki Yong Jeong, Yu Sa Kim; Cancer Res Treat. 2006;38(4):218-223. Published online December 31, 2006; DOI: https://doi.org/10.4143/crt.2006.38.4.218

Abstract PDF PubReader ePub

Purpose

The aim of this study was to investigate the prognostic significance of the expression of p53 gene product in operable invasive breast cancer by performing immunohistochemical analysis.

Materials and Methods

Between January 1993 and December 2001, 440 operable invasive breast cancer patients underwent immunohistochemical staining for p53, and we retrospectively analyzed these results together with the clinical outcomes.

Results

The overexpression of p53 was detected in 51.6% of the cases. The overexpression of p53 was inversely correlated with lymph node metastasis (p=0.005). The tumor size, tumor histology, histologic grade, hormonal receptor status and tumor stage were not related to the overexpression of p53. Multivariate Cox regression analysis indicate that lymph node metastasis, tumor size and the p53 expression were the significant prognostic factors for overall survival; lymph node metastasis, the estrogen receptor status and the p53 expression were the significant prognostic factors for relapse free survival. On the subgroup analysis, the p53 non-expressors showed better 7-year overall survival (92.7% vs. 76.7%, respectively, p=0.011) and relapse free survival (74.9% vs. 57.8%, respectively, p=0.032) than did the p53 overexpressors for the patients with lymph node metastasis. However, for the patients without lymph node metastasis, the survival rates were not different for both the p53 non-expressors and the p53 overexpressors.

Conclusion

Immunohistochemical staining of the p53 gene product was an independent prognostic factor for predicting survival of the lymph node positive invasive breast cancer patients.

Citations

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Amber N. Hurson, Mustapha Abubakar, Alina M. Hamilton, Kathleen Conway, Katherine A. Hoadley, Michael I. Love, Andrew F. Olshan, Charles M. Perou, Montserrat Garcia-Closas, Melissa A. Troester
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JAGTAR SINGH, RAMA JAYARAJ, SIDDHARTHA BAXI, MARIANA MILEVA, JOHN SKINNER, NAVNEET K. DHAND, MAHIBAN THOMAS
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Kiran Dahiya, Rakesh Dhankhar
World Journal of Methodology.2016; 6(1): 77. CrossRef
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Preethi Sekar, Jyotsna Naresh Bharti, Jitendra Singh Nigam, Ankit Sharma, Priyanka Bhatia Soni
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An Australian Retrospective Study to Evaluate the Prognostic Role of p53 and eIF4E Cancer Markers in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC): Study Protocol
Jagtar Singh, Rama Jayaraj, Siddhartha Baxi, Mariana Mileva, Justin Curtin, Mahiban Thomas
Asian Pacific Journal of Cancer Prevention.2013; 14(8): 4717. CrossRef
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Asim Kumar Manna, Aparajita Samaddar, Sumit Mitra, Swapan Pathak, Srabani Chakrabarti, Diptendra Kumar Sarkar
Indian Journal of Surgery.2013; 75(3): 204. CrossRef
Exposure to depleted uranium does not alter the co-expression of HER-2/neu and p53 in breast cancer patients
Mais M Al-Mumen, Asad A Al-Janabi, Alaa S Jumaa, Kaswer M Al-Toriahi, Akeel A Yasseen
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Balance between SIRT1 and DBC1 expression is lost in breast cancer
Ji‐Youn Sung, Ranah Kim, Ja‐Eun Kim, Juhie Lee
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Cell Cycle Regulatory Protein Expression Profiles by Adenovirus p53 Infection in Human Papilloma Virus-associated Cervical Cancer Cells: Yong-Seok Lee, Su-Mi Bae, Sun-Young Kwak, Dong-Chun Park, Yong-Wook Kim, Soo-Young Hur, Eun-Kyung Park, Byoung-Don Han, Young-Joo Lee, Chong-Kook Kim, Do Kang Kim, Woong-Shick Ahn; Cancer Res Treat. 2006;38(3):168-177. Published online June 30, 2006; DOI: https://doi.org/10.4143/crt.2006.38.3.168

Abstract PDF PubReader ePub

Purpose

The tumor suppressor gene, p53, has been established as an essential component for the suppression of tumor cell growth. In this study, we investigated the time-course anticancer effects of adenoviral p53 (Adp53) infection on human ovarian cancer cells to provide insight into the molecular-level understanding of the growth suppression mechanisms involved in Adp53-mediated apoptosis and cell cycle arrest.

Materials and Methods

Three human cervical cancer cell lines (SiHa, CaSki, HeLa and HT3) were used. The effect of Adp53 infection was studied via cell count assay, cell cycle analysis, FACS, Western blot and macroarray assay.

Results

Adp53 exerts a significant role in suppressing cervical cancer cell growth. Adp53 also showed growth inhibitory effects in each cell line, and it induced apoptosis and cell cycle arrest. Adp53 differentially regulated the expression of genes and proteins, and the gene expression profiles in the SiHa cells revealed that the p21, p53 and mdm2 expres sions were significantly up-regulated at 24 and 48 hr. Western blot shows that the p21 and p53 expression-levels were significantly increased after Adp53 infection. In addition, in all cell lines, both the CDK4 and PCNA protein expression levels were decreased 48 h after Adp53 infection. Cell cycle arrest at the G1 phase was induced only in the SiHa and HeLa cells, suggesting that exogenous infection of Adp53 in cancer cells was significantly different from the other HPV-associated cervical cancer cells.

Conclusion

Adp53 can inhibit cervical cancer cell growth through induction of apoptosis and cell cycle arrest, as well as through the regulation of the cell cycle-related proteins. The Adp53-mediated apoptosis can be employed as an advanced strategy for developing preferential tumor cell-specific delivery.

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Health‐promoting bioactivity and in vivo genotoxicity evaluation of a hemiepiphyte fig, Ficus dubia
Uthaiwan Suttisansanee, Pornsiri Pitchakarn, Pisamai Ting, Woorawee Inthachat, Parunya Thiyajai, Daraphan Rodthayoy, Jirarat Karinchai, Bhanumas Chantarasuwan, Onanong Nuchuchua, Piya Temviriyanukul
Food Science & Nutrition.2021; 9(4): 2269. CrossRef
Comprehensive Data of P53 R282 Gene Mutation with Human Papillomaviruses (HPV)-Associated Oral Squamous Cell Carcinoma (OSCC)
Tipaya Ekalaksananan, Weerayut Wongjampa, Pensiri Phusingha, Jureeporn Chuerduangphui, Patravoot Vatanasapt, Supannee Promthet, Natcha Patarapadungkit, Chamsai Pientong
Pathology & Oncology Research.2020; 26(2): 1191. CrossRef
Etoposide radiosensitizes p53-defective cholangiocarcinoma cell lines independent of their G2 checkpoint efficacies
Arunee Hematulin, Sutiwan Meethang, Kitsana Utapom, Sopit Wongkham, Daniel Sagan
Oncology Letters.2018;[Epub] CrossRef
Effect and Safety of Recombinant Adenovirus-p53 Transfer Combined with Radiotherapy on Long-Term Survival of Locally Advanced Cervical Cancer
Xing Su, Wen-juan Chen, Shao-wen Xiao, Xiao-fan Li, Gang Xu, Jian-ji Pan, Shan-wen Zhang
Human Gene Therapy.2016; 27(12): 1008. CrossRef
Celecoxib, a COX-2 Selective Inhibitor, Induces Cell Cycle Arrest at the G2/M Phase in HeLa Cervical Cancer Cells
Agustina Setiawati
Asian Pacific Journal of Cancer Prevention.2016; 17(4): 1655. CrossRef
Cisplatin sensitivity and mechanisms of anti-HPV16 E6-ribozyme on cervical carcinoma CaSKi cell line
Zhiguo Rao, Jianfei Gao, Bicheng Zhang, Bo Yang, Jiren Zhang
The Chinese-German Journal of Clinical Oncology.2012; 11(4): 237. CrossRef

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Thymidylate Synthase, Thymidine Phosphorylase, VEGF and p53 Protein Expression in Primary Colorectal Cancer for Predicting Response to 5-fluorouracil-based Chemotherapy: Myung-Ju Ahn, Jung-Hye Choi, Ho-Suk Oh, Young-Yeul Lee, In-Soon Kim, Il-Young Choi, Kang-Hong Lee, Kang-Won Song, Chan-Kum Park; Cancer Res Treat. 2005;37(4):216-222. Published online August 31, 2005; DOI: https://doi.org/10.4143/crt.2005.37.4.216

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Purpose

In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival.

Materials and Methods

The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated.

Results

Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy.

Conclusion

These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.

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Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors
Laura Grumetti, Rita Lombardi, Federica Iannelli, Biagio Pucci, Antonio Avallone, Elena Di Gennaro, Alfredo Budillon
Cancers.2022; 14(3): 695. CrossRef
Immunoexpression of TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers and its correlation with degree of differentiation, tumor staging and prognostic factors in colorectal adenocarcinoma: a retrospective longitudinal study
Wilson Roberto Batista, Gianni Santos, Flávia Maria Ribeiro Vital, Delcio Matos
Sao Paulo Medical Journal.2019; 137(1): 33. CrossRef
Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5‑fluorouracil‑based chemotherapy: A meta‑analysis
Jia Che, Lun Pan, Xiangling Yang, Zhiting Liu, Lanlan Huang, Chuangyu Wen, Aihua Lin, Huanliang Liu
Molecular and Clinical Oncology.2017;[Epub] CrossRef
Does anti-p53 antibody status predict for clinical outcomes in metastatic colorectal cancer patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy?
Hiroki Osumi, Eiji Shinozaki, Mitsukuni Suenaga, Yosuke Kumekawa, Mariko Ogura, Masato Ozaka, Satoshi Matsusaka, Keisho Chin, Noriko Yamamoto, Nobuyuki Mizunuma
BMC Cancer.2015;[Epub] CrossRef
Comparison of thymidine phosphorylase expression and prognostic factors in gallbladder and bile duct cancer
Hye Sung Won, Myung Ah Lee, Eun-Seon Chung, Dong-Goo Kim, Young Kyoung You, Tae Ho Hong, In-Seok Lee
BMC Cancer.2010;[Epub] CrossRef

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Expression of c-kit and p53 in Non-small Cell Lung Cancers: Jinyoung Yoo, Chi Hong Kim, So Hyang Song, Byoung Yong Shim, Youn Ju Jeong, Meyung Im Ahn, Sung Whan Kim, Deog Gon Cho, Min Seop Jo, Kyu Do Cho, Hong Joo Cho, Hoon-Kyo Kim; Cancer Res Treat. 2004;36(3):167-172. Published online June 30, 2004; DOI: https://doi.org/10.4143/crt.2004.36.3.167

Abstract PDF PubReader ePub

Purpose

Increasing experimental evidence indicates that abnormal expression of c-kit may be implicated in the pathogenesis of a variety of solid tumors. It has been reported that over 70% of small cell lung cancer (SCLC) contain the c-kit receptor. In the present study, a c-kit analysis has been extended to non-small cell lung cancer (NSCLC). The expressions of p53, vascular endothelial growth factor (VEGF) and cd34, in addition to c-kit, were evaluated to investigate the correlations between these proteins and to determine their potential relationships with the clinicopathological data.

Materials and Methods

Paraffin-embedded tumor sections, obtained from 147 patients with NSCLC, were immunohistochemically investigated using anti-c-kit, anti-p53, anti-VEGF and anti-cd34 antibodies.

Results

c-kit was expressed in 40 (27%) of the tumors examined: 27% of the adenocarcinomas, 27% of the squamous cell carcinomas and 29% of the undifferentiated carcinomas. p53 and VEG F immunoreactivities were present in 107 (73%) and 110 (75%) carcinomas, respectively. Anti-cd34 was negative in all samples. No associations were established among these proteins. The c-kit, however, showed a strong correlation with the T factor: T1 (n=11), 0%; T2 (n=49), 16% and T3 (n=87), 37% (p=.006).

Conclusion

It is suggested that in NSCLC c-kit is expressed relatively frequently and may become a therapeutic target for the patients with inoperable or recurrent c-kit positive tumors. The alterations in p53 probably constitute an early event, whereas the activated c-kit may contribute to tumor progression.

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Clinical and Prognostic Significance of CD117 in Non-Small Cell Lung Cancer: A Systemic Meta-Analysis
Ying Su, Ru Chen, Zhongcheng Han, Rong Xu, Lili Ma, Reyina Wufuli, Hongbo Liu, Fang Wang, Lei Ma, Rui Chen, Jiang Liu
Pathobiology.2021; 88(4): 267. CrossRef
A review of predictive, prognostic and diagnostic biomarkers for non-small-cell lung cancer: towards personalised and targeted cancer therapy
Ernest Osei, Julia Lumini, Dinindu Gunasekara, Beverley Osei, Akua Asare, Raymond Laflamme
Journal of Radiotherapy in Practice.2020; 19(4): 370. CrossRef
Design, synthesis and anti-cancer activity of pyrrole-imidazole polyamides through target-downregulation of c-kit gene expression
Mi Zhang, Jing Liang, Shi-Kun Jiang, Ling Xu, Yan-Ling Wu, Annoor Awadasseid, Xiao-Yin Zhao, Xu-Qiong Xiong, Hiroshi Sugiyama, Wen Zhang
European Journal of Medicinal Chemistry.2020; 207: 112704. CrossRef
Relative influence of c-Kit expression and epidermal growth factor receptor gene amplification on survival in patients with non-small cell lung cancer
HUI XIAO, JUAN WANG, YANAN LIU, LI LI
Oncology Letters.2014; 8(2): 582. CrossRef
Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer
Misun Park, Won Kyu Kim, Meiying Song, Minhee Park, Hyunki Kim, Hye Jin Nam, Sung Hee Baek, Hoguen Kim
Clinical Cancer Research.2013; 19(18): 4961. CrossRef

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The Expression of c-myc, bcl-2 and p53 Proteins in Adenocarcinomas of Lung: Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang; Cancer Res Treat. 2004;36(2):146-150. Published online April 30, 2004; DOI: https://doi.org/10.4143/crt.2004.36.2.146

Abstract PDF PubReader ePub

Purpose

c-myc, bcl-2 and p53 are known to regulate apoptosis. There has been growing interest in analyzing their contribution to the pathogenesis and prognosis in a variety of human cancers. This study was undertaken to investigate the expression of these proteins in pulmonary adenocarcinomas and to determine their relationship with clinicopathologic parameters and survival.

Materials and Methods

Archival tumor tissues from 61 patients with adenocarcinoma of lung were analyzed by immunohistochemistry for the expression of c-myc, bcl-2 and p53 proteins. Clinical information was obtained through the computerized retrospect database from the tumor registry.

Results

Of 61 patients, 32 were men and 29 women with the median age 63 years. 4 had stage I disease, 2 had stage II disease and 55 had stage III disease. The expression of c-myc protein was identified in 13% (8/61) tumors, bcl-2 protein was detected in 1.6% tumors (1/61) and p53 was detected in 77% (47/71) tumors. The association of the expression of c-myc, bcl-2 and p53 was not detected. The survival time was longer in patients expressing c-myc protein than in patients without the c-myc protein expression (p=.045). Neither bcl-2 nor p53 showed the correlation to clinicopathologic variables.

Conclusion

Our data suggest the involvement of p53 alteration in the pathogenesis of lung adenocarcinoma. The c-myc expression in some tumors indicates that c-myc alone may not contribute critically to the development and/or the progression of these tumors. It, however, correlated to the survival time, suggesting the c-myc expression as a favorable prognostic factor possibly through the apoptosis pathway.

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The transcriptional repression activity of STAF65γ is facilitated by promoter tethering and nuclear import of class IIa histone deacetylases
Feng-Shu Hsieh, Nai-Tzu Chen, Ya-Li Yao, Shi-Yun Wang, Jeremy J.W. Chen, Chien-Chen Lai, Wen-Ming Yang
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms.2014; 1839(7): 579. CrossRef
Expression of Matrix Metalloproteinase-9 Correlates with Poor Prognosis in Human Malignant Fibrous Histiocytoma
Jinyoung Yoo, Ji Han Jung, Seok Jin Kang, Chang Suk Kang
Cancer Research and Treatment.2004; 36(6): 384. CrossRef

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Review Article

p63 and p73 in Tumor Suppression and Promotion: Frank D. McKeon; Cancer Res Treat. 2004;36(1):6-12. Published online February 29, 2004; DOI: https://doi.org/10.4143/crt.2004.36.1.6

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The recent discovery of two genes, termed p63 and p73, encoding transcription factors highly homologous to p53 presents unexpected challenges and opportunities for the understanding and treatment of cancers. The questions raised are many but center on determining whether these new genes possess novel tumor suppressor functions, cooperate with p53, or impart oncogenic effects. At present there is considerable discord in the field concerning these concepts with some favoring a tumor suppressor role for the p53 family members and others an oncogenic influence. In support of a tumor suppressor role is the ability of p73 and p63 isoforms to transactivate p53 target genes and the large body of work linking p73, and to some extent p63, in apoptotic events in response to cellular stresses generally considered the purview of p53. More recently, p73 has been implicated in cell death following T cell activation, the response of cancers to chemotherapy, and finally, along with p63, to the function of p53 itself. Opposing this view is the fact that the p73 and p63 genes are rarely mutated in cancers and the stark absence of tumors in the p73 null mouse. Moreover, the high expression of dominant negative (dn) versions of the p73 and p63 proteins supports an anti-p53 function and therefore possibly an oncogenic effect. Indeed, the p63 gene is located in a region of chromosome three amplified in squamous cell carcinomas and the number of reports of dn-p63 overexpression in these diseases is increasing. This review will examine both sides of these arguments in an attempt to decipher common themes and to identify opportunities these genes represent for understanding tumorigenesis.

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p53 amyloid pathology is correlated with higher cancer grade irrespective of the mutant or wild-type form
Shinjinee Sengupta, Namrata Singh, Ajoy Paul, Debalina Datta, Debdeep Chatterjee, Semanti Mukherjee, Laxmikant Gadhe, Jyoti Devi, Yeshwanth Mahesh, Mohit Kumar Jolly, Samir K. Maji
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A Newly Defined Pyroptosis-Related Gene Signature for the Prognosis of Bladder Cancer
Weikang Chen, Wenhao Zhang, Tao Zhou, Jian Cai, Zhixian Yu, Zhigang Wu
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ΔNp63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis
Sunyoung Park, Suji Lee, Jungho Kim, Geehyuk Kim, Kwang Hwa Park, Tae Ue Kim, Dawn Chung, Hyeyoung Lee, Hiromu Suzuki
PLOS ONE.2019; 14(4): e0214867. CrossRef
Identification of a novel microRNA-mRNA regulatory biomodule in human prostate cancer
Yanqiong Zhang, Funeng Jiang, Huichan He, Jianheng Ye, Xia Mao, Qiuyan Guo, Shu-lin Wu, Weide Zhong, Chin-Lee Wu, Na Lin
Cell Death & Disease.2018;[Epub] CrossRef
p53 family members — important messengers in cell death signaling in photodynamic therapy of cancer?
Pilar Acedo, Joanna Zawacka-Pankau
Photochemical & Photobiological Sciences.2015; 14(8): 1389. CrossRef

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Original Articles

Growth Suppression and Induction of Chemosensitivity in Human Gallbladder Epithelial Carcinoma Cells (GBCE) by Adenovirus-Mediated Transfer of the Wild-type p53 Gene: Sung Bae Kim, Myung Hwan Kim, Sung Koo Lee, Tae Won Kim, Cheolwon Suh, Jeong Sik Shin, Jung Sun Park, Eun Soon Kim, Gyungyub Gong, Jung Shin Lee, Woo Kun Kim, Sang Hee Kim; Cancer Res Treat. 2003;35(6):521-527. Published online December 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.6.521

Abstract PDF: PURPOSE
Mutations in the p53 gene are reported in 50~90% of gallbladder and bile duct cancer, and have been implicated in chemoresistance. We undertook this study to determine whether the introduction of the wild type p53 gene into GBCE (human gallbladder cancer cell line with a heterozygous p53 mutation) by an adenoviral vector could increase the sensitivity of the cell to 5-FU, a commonly used drug in the treatment of gallbladder cancer. MATERIALS AND METHODS: GBCE cells were transfected with either Ad/p53 or Ad/E1 in the presence of 5-FU. Gene expression was confirmed by western blotting. Nude mice were injected subcutaneously with GBCE cells. When tumors formed, intratumoral injection of Ad/p53 was performed. Reduction of tumor size was compared in two weeks of Ad/p53 gene transfection. RESULTS: Ad/53 transfection induced a dose-dependent inhibition of tumor growth. Tumor colony formation was more inhibited with p53 gene transfection than with mock transfection in the presence of 5-FU. The reduction in tumor size was more pronounced with p53 transfection than with mock infection.
CONCLUSION
These treatment modalities could be utilized in the treatment of p53 mutant human gallbladder cancers.

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Correlation between p53 and Rb Protein Expression and Clinicopathologic Features in Hepatocellular Carcinoma: Mi Jin Gu, Joon Hyuk Choi; Cancer Res Treat. 2003;35(6):514-520. Published online December 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.6.514

Abstract PDF

PURPOSE
Hepatocellular carcinomas (HCC) are one of the most common cancers in Korea. The mechanism of HCC development is still unclear, and the aberration of the tumor suppressor genes in HCC remains to be clarified. MATERIALS AND METHODS: To study the expressions of p53 and Rb protein, and their correlation with the clinicopathological parameters in HCC, 68 patients, with surgically resected hepatocellular carcinomas, were analyzed by an immunohistochemical method. The expressions of p53 and Rb protein were classified into three categorizes, depending on the percentage of stained cells. RESULTS: The expression of the p53 protein was 51.5% (35/68), and was significantly correlated with differentiation (p<0.05). The altered Rb protein expression was 72.2% (49/68). The expressions of p53 and altered Rb protein had no significant correlation with the tumor size, gender, WHO histological pattern, cirrhosis or vascular invasion (p>0.05). There was a positive correlation between p53 and Rb protein overexpression (p<0.05). The expressions of p53 and Rb protein had correlation with the Ki-67 labeling index (p<0.05). CONCLUSION: These findings suggest the aberrant expressions of p53 and Rb protein may play a role in the progression and carcinogenesis of HCC.

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Clinical significance of down-regulated HINT2 in hepatocellular carcinoma
Dong-Kai Zhou, Xiao-Hui Qian, Jun Cheng, Ling-Hui Chen, Wei-Lin Wang
Medicine.2019; 98(48): e17815. CrossRef

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Clinical Implications of VEGF and p53 Expression in Squamous Cell Carcinoma of the Cervix Treated with Radiation Therapy: Jin Oh Kang, Seong Eon Hong, Dong Wook Kang; Cancer Res Treat. 2003;35(5):440-444. Published online October 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.5.440

Abstract PDF

PURPOSE
The present study was designed to analyze the relationship between vascular endothelial growth factor (VEGF) and p53, and their impact on clinical outcome in squamous cell carcinoma of the cervix treated with radiation therapy. MATERIALS AND METHODS: This immunohistochemical study involved 23 patients with available paraffin blocks among 46 patients who were treated during the period from 1994 to 1997 in Eulji University Hospital in Korea. Anti-VEGF mouse monoclonal antibody and DO-7 anti- p53 mouse monoclonal antibody were used as the primary antibodies. Antibody binding was detected with a LSAB kit. Staining was defined as positive for VEGF and p53, when more than 10% and 5% of the tumor cells were stained out of 500 cells counted, respectively. RESULTS: FIGO stage (p=0.05) and tumor size (p=0.04) were significant prognostic factors for survival. p53 expression was present in 17 (77%) cases. There was no significant relationship between p53 staining and the clinicopathologic factors, such as FIGO stage (p=0.98), tumor size (p=0.43), lymph node status (p=0.82), parametrial invasion (p=0.96), and age (p=0.18). The five year survival rates according to the p53 expression status were 80% for the p53 negative group and 66% for the p53 positive group (p=0.58). Positive VEGF expression was observed in 11 (47%) of the total of 23 patients. Statistical evaluation of VEGF expression according to stage (p=0.36), tumor size(p=0.11), lymph node status (p=0.82), parametrial invasion (p=0.49), and age (p=0.55) revealed no significant difference in any of these parameters. The five year survival rates according to the VEGF expression status were 89% for the VEGF negative group and 41% for the VEGF positive group (p=0.07). CONCLUSION: We suggest that VEGF expression may have an effect on the prognosis of cervix cancer patients treated with radiation therapy, and further evaluation with a large sample size is warranted.

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Research advances in signaling pathways related to the malignant progression of HSIL to invasive cervical cancer: A review
Huifang Wang, Chang Liu, Keer Jin, Xiang Li, Jiaxin Zheng, Danbo Wang
Biomedicine & Pharmacotherapy.2024; 180: 117483. CrossRef

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Cell-Specific Growth Inhibition of Human Cervical Cancer Cell by Recombinant Adenovirus p53 in vitro and in vivo: Su Mi Bae, Yong Wook Kim, Joo Hee Yoon, Jin Young Yoo, Young Seok Seo, Sang Lyun Nam, Joon Mo Lee, Sung Eun Namkoong, Chong Kook Kim, Yong Wan Kim, Woong Shick Ahn; Cancer Res Treat. 2003;35(3):181-190. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.181

Abstract PDF

PURPOSE
Despite the significance of the p53 adenoviral vector in cancer gene therapy, an advanced strategy for the development of preferential tumor cell-specific delivery and the long-term persistent gene expression control of p53 are required. In this study, the time-course expression patterns of p53 and E6, on cervical cancer cells, were investigated to obtain a molecular level understanding of the cell-dependent tumor growth suppression effects of a recombinant adenovirus expressing p53, both in vitro and in vivo. MATERIALS AND METHODS: The expressions of p53 and E6 in CaSki, SiHa, HeLa, HeLaS3, C33A and HT3 cervical cancer cell lines were examined. After infection with AdCMVp53, the cell growth inhibition was studied via cell count, MTT and Neutral red assays. After transfecting the AdCMVp53 and AdCMVLacZ into the cancer cells-xenografted nude mice, the anti-tumor effects were investigated for one month. RESULTS: The p53 protein levels were more notably expressed in the CaSki and HeLa than in the SiHa and HeLaS3 On day 6, the p53 was only detected in the HeLaS3. In contrast, the p53 expression was highly maintained in the C33A and HT3. The E6 mRNA levels gradually decreased in only the CaSki and HeLa. The growth suppression effects also showed cell-dependent patterns, which were consistent with the reciprocal expression patterns of p53 and E6. After transfection of the AdCMVp53, into the CaSki- and SiHa-xenografted nude mice, the tumor size was remarkably decreased in the SiHa cells as compared to that in the AdCMVLacZ transfected mice, indicating cell-specific growth inhibition patterns.
CONCLUSION
The adenovirus-mediated p53 gene transfection was very effective both in vitro and in vivo. Also, the anti-tumor effects were accomplished via the differential role of p53-specific apoptotic cell death, which was dependent on the cervical cancer cell line.

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Immunization with Adenoviral Vectors Carrying Recombinant IL-12 and E7 Enhanced the Antitumor Immunity against Human Papillomavirus 16-associated Tumor
Eun-Kyung Park, Young-Wook Kim, Joon-Mo Lee, Sung-Eun NamKoong, Do-Gang Kim, Heung-Jae Chun, Byoung-Don Han, Su-Mi Bae, Hyun-Sun Jin, Jeong-Im Sin, Woong-Shick Ahn
Cancer Research and Treatment.2005; 37(1): 63. CrossRef

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Differential Sensitivity of Taxol-induced Apoptosis in U2OS and SaOS2 Osteogenic Sarcoma Cells: Jung Hye Kim, Byung Rho Chin, Seong Yong Kim, Jae Ryong Kim, Suk Hwan Baek; Cancer Res Treat. 2003;35(2):148-153. Published online April 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.2.148

Abstract PDF

PURPOSE
Taxol (Paclitaxel) is a new generation of chemotherapeutic drug proven to be effective in the treatment of many cancers. In this study, to further demonstrate the differential effect of the tumor suppressor gene, p53, on the Taxol-induced apoptosis in osteogenic sarcoma cell lines, we used p53-defected SaOS2 cells and wild type p53-expressed U2OS cells. MATERIALS AND METHODS: The cell viability was measured by the XTT assay. To examine whether the differential expressions of p53, in U2OS and SaOS2 cells, were associated with Taxol-induced apoptosis, DNA fragmentation assays were performed on both cytosolic and genomic DNA. Since the cleavage of poly (ADP-ribose) polymerase (PARP) is primarily responsible for apoptosis, the cleavage of PARP, and the expression of cyclin B1, polo-like kinase, Bax, Bcl-xL, Bcl-2 in U2OS and SaOS2 cells were compared by Western blot analyses. RESULTS: The cell viability of the p53-defected SaOS2 cells was markedly decreased with Taxol treatment. Whereas, the cell viabilities due to 6-mercaptopurine and adriamycin were no different between the U2OS and SaOS2 cells. Treatment with Taxol induced a ladder- like pattern of DNA fragments, which is a biochemical hallmark of apoptosis, consisting of multiples of approximately 180-200 base pairs, in a dose-dependent manner in the SaOS2 cells, but insignificantly with the U2OS cells. When the cells were treated with Taxol, the 89 kDa cleavage product of PARP clearly appeared as a function of time in the SaOS2 cells, but not in the U2OS cells. The Taxol-induced apoptosis in p53 defected-osteogenic sarcoma cells was associated with the PARP cleavage as a result of the increased activity of caspase 3, and the high expressions of cyclin B1 and PLK. Bax, as a proapoptotic factor, was increased in the SaOS2cells, but the Bcl-xL and Bcl-2 were decreased when the cells were exposed to 10miceoM Taxol. CONCLUSION: From these results, it was concluded that p53-defected SaOS2 cells are much more sensitive to Taxol-induced apoptosis than p53-expressed U2OS cells.

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Paulina Sobierajska, Benita Wiatrak, Paulina Jawien, Maciej Janeczek, Katarzyna Wiglusz, Adam Szeląg, Rafal J. Wiglusz
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Xiaofeng Dai, Danjun Wang, Jianying Zhang
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Heather L. Martin, Matthew Adams, Julie Higgins, Jacquelyn Bond, Ewan E. Morrison, Sandra M. Bell, Stuart Warriner, Adam Nelson, Darren C. Tomlinson, Maria A. Deli
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Cancer Research and Treatment.2004; 36(6): 395. CrossRef

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Polymorphisms of p53, p21 and IRF-1 and Cervical Cancer Susceptibility in Korean Women: Sung Jong Lee, Sung Eun Namkoong, Won Chul Lee, Jae Woong Sul, Sun Ha Jee, Youn Kyoung You, Jong Eun Lee, Jong Sup Park; Cancer Res Treat. 2002;34(5):357-364. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.357

Abstract PDF

PURPOSE
The aim of this study was to identify gene- gene and gene-environmental factor on cervical carcinogenesis in Korean women.
MATERIALS AND METHODS
We evaluated 185 women patients who had cervical cancer with 345 normal control healthy women. The single nucleotide polymorphisms (SNPs) of the p53 codon 72, the p21 codon 31 and the IRF-1 intron 6 were evaluated from extracted DNA of peripheral blood with an automatic DNA sequencer. The difference of each SNP, gene-gene and gene-environmental interaction between normal controls and patients, were evaluated in an adjusted environmental background.
RESULTS
With regard to environmental factors, the cervical cancer increased in the women with a lower level of education, a younger age at first sexual intercourse and with the increased number of children borne. The women who had p53 (Arg/Arg), IRF-1 (T/T) and an education of less than 6 years showed a 14.7 fold increased risk of cervical cancer than those women who had p53 (~Pro), IRF-1 (~C) and an education of more than 15 years. The women who had p53 (Arg/Arg), p21 (Ser/Ser) and more than 3 children showed a 6.4 fold increased risk of cervical cancer than those women who had p53 (~Pro), p21 (~Arg) and had borne no child. The women who had p53 (Arg/Arg), IRF-1 (T/T) and had experience of first sexual intercourse before the age of 22-years showed a 5.5 fold increased risk of cervical cancer than those women who had p53 (~Pro), IRF-1 (~C) and had experience of first sexual intercourse after the age of 26-years.
CONCLUSION
We found that the level of education, the age at first intercourse, and the number of children borne, were independent risk factors in cervical carcinogenesis. The specific combination of p53, p21 and IRF-1 gene-gene and gene-environmental interactions were significantly noted in the cervical carcinogenesis of Korean women.

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Distinctive cell cycle regulatory protein profiles by adenovirus delivery of p53 in human papillomavirus-associated cancer cells
H.-S. JIN, S.-M. BAE, Y.-W. KIM, J.-M. LEE, S.-E. NAMKOONG, B.-D. HAN, Y.-J. LEE, C.-K. KIM, H.-J. CHUN, W.-S. AHN
International Journal of Gynecological Cancer.2006; 16(2): 698. CrossRef
Cell Cycle Regulatory Protein Expression Profiles by Adenovirus p53 Infection in Human Papilloma Virus-associated Cervical Cancer Cells
Yong-Seok Lee, Su-Mi Bae, Sun-Young Kwak, Dong-Chun Park, Yong-Wook Kim, Soo-Young Hur, Eun-Kyung Park, Byoung-Don Han, Young-Joo Lee, Chong-Kook Kim, Do Kang Kim, Woong-Shick Ahn
Cancer Research and Treatment.2006; 38(3): 168. CrossRef
Cellular process classification of human papillomavirus-16-positive SiHa cervical carcinoma cell using Gene Ontology
W. S. Ahn, M.-J. Seo, S. M. Bae, J. M. Lee, S. E. Namkoong, C. K. Kim, Y.-W. Kim
International Journal of Gynecological Cancer.2005; 15(1): 94. CrossRef

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Clinical Significance of p53, P-glycoprotein, and Glutathione S transferase-pi in Advanced Non-Small Cell Lung Cancer: Young Don Joo, Chang Hak Sohn; Cancer Res Treat. 2002;34(1):34-40. Published online February 28, 2002; DOI: https://doi.org/10.4143/crt.2002.34.1.34

Abstract PDF: PURPOSE
A retrospective study was performed o define the clninical significance of p53, P-glycoprotein (Pgp), and Glutathione S transferase-pi (GST-pi) immunohistochemical (IHC) expression in advanced non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS
We reviewed fifty seven patients with advanced NSCLC who had undergone surgical resection or bronchoscopic biopsy between March 1997 and March 1999. IHC staining for p53, GST-pi, and Pgp was performed using formalin-fixed, paraffin-embedded specimens of the fifty seven patients.
RESULTS
The IHC expression rate was 63% for p53, 28% for Pgp, and 53% for GST-pi, respectively. The median survival of the fifty seven patients was 45 weeks and the response rate was 38.6% (partial response, 22/57). The chemotherapy response and median survival of the p53 negative group (57% and 61 weeks) were better than those demonstrated by the p53 positive group (28% and 21 weeks) (p<0.05). Additionally, the GST-pi negative group showed a greater improvement of survival and response rate than the positive group (p<0.05). Pgp expression status appeared to have no significant differential effect on chemotherapy response and survival.
CONCLUSION
These results suggest that immunohisto chemical staining of p53 and GST-pi may be useful in predicting the response to chemotherapy as well as survival in advanced NSCLC. However, this study is limited by its retrospective nature and the small numbers of tumors studied from a heterogenous group of patients.

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Clinical Analysis of PTEN, p53 and Her-2/neu Expressions in Thyroid Cancers: Jeong Soo Kim, Ja Seong Bae, Kee Hwan Kim, Chang Hyeok Ahn, Se Jeong Oh, Hae Myung Jeon, Keun Woo Lim, Chung Soo Chun; Cancer Res Treat. 2001;33(5):433-437. Published online October 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.5.433

Abstract PDF

PURPOSE
The dual-specificity phosphatase PTEN/ MMAC1/TEP1 has recently been identified as the tumor suppressor gene most frequently mutated and/or deleted in human tumors. However, PTEN mutations have rarely been detected in sporadic thyroid cancers. Therefore, this study investigated the PTEN expression of thyroid cancer and the relationship between PTEN, clinical status and other biologic factors such as HER-2/neu and p53.
MATERIALS AND METHODS
The study samples consisted of 62 thyroid cancer specimens and 24 benign thyroid tumor specimens from patients who were operated on the Department of Surgery, Uijongbu St. Mary's hospital during the 5 years from January 1995 until January 2000. All tumors were studied by immunohistochemical staining using monoclonal antibodies against PTEN, HER-2/neu and p53. The results were analyzed statistically.
RESULTS
PTEN protein was found to be under-expressed more frequently in thyroid cancers (29%) than in benign thyroid tumors (4.2%). The reduction in PTEN expression in thyroid cancers was not significantly related with the recorded clinical factors such as size, age, lymph node metastasis and p53, except for HER-2 which was found to be significantly related (p=0.001). HER-2 over- expression was noted in thyroid cancer (83.8%) more frequently than in benign tumors (16.7%).
CONCLUSION
This study has demonstrated that the under-expression of PTEN protein and the over-expression of HER-2 protein may play a role in the carcinogenesis and development of thyroid cancer.

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Man Lu, Hanqing Liu, Bilian Zheng, Shengrong Sun, Chuang Chen
Cancers.2022; 14(20): 5117. CrossRef
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L.A. Jonker, C.A. Lebbink, M.C.J. Jongmans, R.A.J. Nievelstein, J.H.M. Merks, E.J.M. Nieveen van Dijkum, T.P. Links, N. Hoogerbrugge, A.S.P. van Trotsenburg, H.M. van Santen
European Thyroid Journal.2020; 9(5): 234. CrossRef
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Yong Wook Kim, Su Mi Bae, Joon Mo Lee, Sung Eun Namkoong, Sei Jun Han, Byoung Rai Lee, Insu P. Lee, Sang Hee Kim, Young Joo Lee, Chong Kook Kim, Yong-Wan Kim, Woong Shick Ahn
Cancer Research and Treatment.2004; 36(5): 315. CrossRef

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E-Cadherin Expression and p53 Alterations in Soft Tissue Sarcomas: A Possible Role in Epithelial Differentiation: Jin Young Yoo, Seok Jin Kang, Woong Shick Ahn, Byung Kee Kim; Cancer Res Treat. 2001;33(4):343-349. Published online August 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.4.343

Abstract PDF

PURPOSE
We investigated the expressions of E- Cadherin and p53 in soft tissue tumors to determine their significance in sarcoma development and/or progression and to assess their potential correlation with epithelial features.
MATERIALS AND METHODS
A total of 79 soft tissue sarcomas, including 10 tumors comprising epithelial components, were studied immunohistochemically in paraffin-embedded tissue sections. Further analysis was performed on 61 tumors by the application of a polymerase chain reaction technique and a direct sequence analysis procedure applied to exons 5 through 8 in the p53 gene.
RESULTS
E-Cadherin was expressed at the cell-cell boundaries in 8 (10%) tumors: 5 of grade 2 and 3 of grade 3. Of these, six (being 60% of the total of 10 tumors containing epithelial elements) contained and two did not contain histologic evidence of epithelial differentiation. Overexpression of p53 was detected in 26 (33%) samples, 7 of which demonstrated mutations in the p53 gene. No association was established between E-Cadherin immunoreactivities and p53 abnormalities. Tumor grade was found to be strongly correlated with p53 alterations (p=0.01) but not with E-Cadherin expression (p=0.09).
CONCLUSION
These data confirm a role for altered p53 in the pathogenesis of soft tissue sarcomas and suggest a possible role for E-Cadherin in the maintenance of epithelial architecture in these tumors regardless of p53 status.

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Meloxicam Modulates Oxidative Stress Status, Inhibits Prostaglandin E2, and Abrogates Apoptosis in Carbon Tetrachloride–Induced Rat Hepatic Injury
Mohamed Edfawy, Memy H. Hassan, Ahmed Mansour, Abdel-Aziz Hamed, Hebat Allah A. Amin
International Journal of Toxicology.2012; 31(3): 276. CrossRef
Antioxidant and antiapoptotic effects of capsaicin against carbon tetrachloride-induced hepatotoxicity in rats
Memy H Hassan, Mohamed Edfawy, Ahmed Mansour, Abdel-Aziz Hamed
Toxicology and Industrial Health.2012; 28(5): 428. CrossRef
Expression of c-kit and p53 in Non-small Cell Lung Cancers
Jinyoung Yoo, Chi Hong Kim, So Hyang Song, Byoung Yong Shim, Youn Ju Jeong, Meyung Im Ahn, Sung Whan Kim, Deog Gon Cho, Min Seop Jo, Kyu Do Cho, Hong Joo Cho, Hoon-Kyo Kim
Cancer Research and Treatment.2004; 36(3): 167. CrossRef
Expression of Caspase-3 and c-myc in Non-Small Cell Lung Cancer
Jin young Yoo, Chi Hong Kim, So Hyang Song, Byoung Yong Shim, Youn Ju Jeong, Meyung Im Ahn, Suji Kim, Deog Gon Cho, Min Seop Jo, Kyu Do Cho, Hong Joo Cho, Seok Jin Kang, Hoon Kyo Kim
Cancer Research and Treatment.2004; 36(5): 303. CrossRef
The Expression of c-myc, bcl-2 and p53 Proteins in Adenocarcinomas of Lung
Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang
Cancer Research and Treatment.2004; 36(2): 146. CrossRef

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Expression of Cyclin-dependent Kinase Inhibitor p21(WAF1/CIP1) in Non-small Cell Lung Carcinomas: Relationship with p53 Status and Proliferative Activity: Na Hye Myong; Cancer Res Treat. 2001;33(4):329-334. Published online August 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.4.329

Abstract PDF: PURPOSE
The objectives of this study are to elucidate the level of p21(WAF1/CIP1) expression in non-small cell lung carcinomas (NSCLCs) and to investigate the relationship between the p21(WAF1/CIP1) expression and clinicopathologic features; p53 overexpression; and proliferative activity measured by Ki-67 expression.
MATERIALS AND METHODS
The expressions of p21(WAF1/CIP1), p53, and Ki-67 proteins were analyzed by immunohistochemistry in 45 formalin-fixed and paraffin-embedded NSCLC specimens. 43 patients underwent curative resections and 2 patients had bronchoscopic biopsy specimens only. The correlations between p21(WAF1/CIP1) immunoexpression and p53 status; Ki-67 proliferative activity; and clinicopathologic parameters were analyzed statistically by chi-square or Fisher's exact test.
RESULTS
p21(WAF1/CIP1) expression in the carcinoma cells was found in 28 (62%) of 45 cases. There was no significant correlation between p21(WAF1/CIP1) expression and abnormal accumulation of p53 protein. In 16 (36%) of 45 cases, p21(WAF1/CIP1) was expressed inde pendently of p53 overexpressions. p21WAF1/CIP1 expression was not associated with patient sex, smoking history, pathological stage, tumor size, histological grade or type. However, p21WAF1/CIP1 immunoreactivity was significantly higher in older individuals over 59 years and tended to occur more intensely in the more highly differentiated portion of the squamous carcinoma. Also, a positive correlation between p21WAF1/CIP1 and Ki-67 expression was observed.
CONCLUSIONS
The present findings overall suggest that aberrations in the relationship between p21(WAF1/CIP1) and p53 expressions may be important in the development of NSCLCs; that a p53-independent pathway may be substantially involved in the induction of p21(WAF1/CIP1) expression in NSCLCs; and that the proliferative activity of lung cancers might be dependent on positive control of the cell cycle by p21(WAF1/CIP1).

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p53 Codon 72 Polymorphism and Cervical Adenocarcinoma Risk in Korean Women: Jeong Hwa Kim, Ju Won Roh, Kyung Sun Kim, Hyeon Jung Jung, Jae Weon Kim, Noh Hyun Park, Yong Sang Song, Soon Beom Kang, Hyo Pyo Lee; Cancer Res Treat. 2001;33(3):243-249. Published online June 30, 2001; DOI: https://doi.org/10.4143/crt.2001.33.3.243

Abstract PDF: PURPOSE
This study was undertaken to analyze whether the p53 codon 72 single nucleotide polymorphism might be correlated with the risk and/or the prognosis of cervical cancer in Korean women.
MATERIALS AND METHODS
Peripheral blood samples derived from patients with cervical squamous cell carcinoma (SCC) (n=68), cervical adenocarcinoma (n=37), cervical intraepithelial neoplasia (CIN) III (n=98) and normal controls (n=98) were examined. Germline genomic DNA was extracted from peripheral blood leukocytes and examined by PCR amplification of the specific alleles assay described by Storey et al.5 Statistical analysis was performed using the Chi-Square test or the Kaplan-Meier survival analysis, logistic regression analysis.
RESULTS
The proportions of individuals who were homozygous for the proline allele, and heterozygous for the two allele, homozygous for arginine allele in each group were 15%, 47%, 38% in the SCC group; 6%, 7%, 24% in the adenocarcinoma group; 7%, 33%, 60% in the CIN III group; and 11%, 38%, 51% in the control group. No significant difference was found between the three groups (p>0.05). However there was a significant difference in the adenocarcinoma group (p<0.05). Arg/Arg homozygote reduced the risk of adenocarcinoma. No significant difference existed in 5-year survival rates in the three groups (p=0.22 in SCC, p=0.91 in adenocarcinoma).
CONCLUSION
These findings suggest that Arg/Arg homozygocity of the p53 codon 72 would be a protective factor against the development of cervical adenocarcinoma.

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Expression of P53, Bcl-2, Bax, and P-glycoprotein in Relation to Chemotherapeutic Response in Patients with Advanced Non-Small-Cell Lung Cance: Suk Young Park, Eun Hee Lee, Kee Won Kim, Chul Seung Kay, Seok Chan Kim, Ji Won Suhr, Kyung Shick Lee; J Korean Cancer Assoc. 2001;33(2):158-162.

Abstract PDF: PURPOSE
To evaluate the relationship between the expressions of p53, bcl-2, bax, and p-glycoprotein and the chemotherapeutic response seen in patients with advanced NSCLC.
MATERIALS AND METHODS
Forty-four patients pathologically proven as NSCLC were reviewed. They had undergone at least two cycles of the same chemotherapeutic agents (cisplatin 60 mg/m2 day 1+ vinorelbine 25 mg/m2 day 1, 8, 21-day cycle) and the clinical response was evaluated by WHO criteria. The expressions of p53, bcl-2, bax, and p-glycoprotein were determined by immunohistochemistry.
RESULTS
Patients recorded as CR (2/44) and PR (20/44) were classified as the responder group (22/44) and stable (17/44) and progression (5/44) as the non-responder group (22/44). Positive expression of p53, bcl-2, bax, and p-glycoprotein were 84.1%, 65.9%, 88.6%, and 61.4% respectively. The expression score of p53 was significantly higher in the non-responder group than that seen in the responder group (8.59+/-1.89 vs 5.32+/-2.15, p<0.05). However, the expression scores of bcl-2, bax, and p-glycoprotein were not significantly correlated with the clinical response.
CONCLUSION
This study suggests that p53 gene mutation plays an important role in the clinical response to chemotherapy including cisplatin and vinorelbine. In future investigations, the correlation with the survival time will be studied.

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Effect of p53 and p16 Protein Expression in Relation to Body Mass Index for Breast Cancer Risk: Mi Kyung Kim, Jung Yeon Kim, Gyung yub Gong, Sei Hyun Ahn; J Korean Cancer Assoc. 2001;33(2):149-157.

Abstract PDF: PURPOSE
This study was conducted to investigate whether breast cancer with p53 protein overexpression (p53+) and loss of p16 protein expression (p16-) shows different body size indicator (height, weight, body mass index) associations as compared with breast tumors without p53 protein overexpression and the loss of p16 expression (p53-, p16+).
MATERIALS AND METHODS
A hospital based case-control study was conducted among 92 women patients and 122 control subjects. The p53 protein overexpression and loss of p16 protein expression in the tissue sections of patients with breast cancer were determined using immunohistochemistry.
RESULTS
A total of 26 tumors (28%) demonstrated p53 overexpression and 35 tumors (46%) showed abnormal p16 expression. The heaviest women had a higher risk with p53- and p16+ breast tumors. The odds ratios (OR) adjusted for age, menopausal status, smoking, and drinking revealed a significant gradient of increasing risk of breast cancer with increasing BMI in p53- and p16+ breast cancer. The adjusted ORs for the highest quintile of BMI was 8.51 with p53+ tumors and 14.2 with p53- tumors, and 55.6 with p16+ tumors and 3.72 with p16- tumors. p53 protein overexpression and the loss of p16 expression did not significantly correlate with nodal status, tumor size, estrogen or progesterone receptor status.
CONCLUSION
The study concluded that a strong association between p53-/p16+ tumors and BMI suggests the occurrence of p53-/p16+ tumors is related with obesity as compared to p53-/p16+ tumors.

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Significance of p53 Immunoreactivity in Squamous Cell Carcinoma of the Cervix Treated with Radiotherapy Alone: Sung Ja Ahn, Ho Sun Choi, Chan Choi, Byung Sik Nah, Woong Ki Chung, Taek Keun Nam; J Korean Cancer Assoc. 2001;33(2):106-112.

Abstract PDF: PURPOSE
We undertook this study to evaluate the significance of p53 immunoreactivity in squamous cell carcinoma of the cervix, treated with radiotherapy alone.
MATERIALS AND METHODS
Immunohistochemical staining of p53 proteins were performed in eighty patients with squamous cell carcinoma of the cervix, and who completed curative radiotherapy between Jan. 1996 and Apr. 1998 at the Department of Therapeutic Radiology, Chonnam National University Hospital. External- beam radiotherapy was combined with intracavitary brachytherapy. Results were analyzed for the end points of pelvic tumor control and distant failure rates. The follow-up time ranged from 7 to 58 months with a median of 40 months.
RESULTS
p53 positive and negative groups involved 45 and 35 patients, respectively, and the positive p53 immunoreactivity rate was 56% (45/80). p53 immunoreactivity showed no significant correlation with age, tumor size, serum tumor marker (SCC), or HPV18 expression, while there was a statistically marginally significant correlation with HPV16 expression. The pelvic tumor control rate of the p53 positive group was 87% and that of p53 negative group was 83% (0.05). The other parameters influencing negatively to the pelvic tumor control and with statistical significance were tumor ulceration and barrel type. Multivariate analysis also showed that p53 immunoreactivity had no prognostic value for pelvic tumor control of the disease, and that the statistically significant factor was tumor ulceration. The treatment failure rate of the p53 positive group was 23% and that of the negative group was 26% (p>0.05).
CONCLUSION
p53 immunoreactivity in the cervix cancer stage IB, II patients seems to have no value as a predictor of tumor behavior after curative radiotherapy.

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Clinical Significance of p53, c-erbB-2, Chromogranin A and PCNA in the Ampullary Carcinoma: Ki Hwan Kim, Sun Whe Kim, Woo Ho Kim, Yong Hyun Park; J Korean Cancer Assoc. 2001;33(1):84-91.

Abstract PDF: PURPOSE
To determine the clinical significance of p53, c-erbB-2, chromogranin A (CgA), proliferating cell nuclear antigen (PCNA) expression in ampullary carcinoma, a retrospective study was performed.
MATERIALS AND METHODS
The cases of 96 patients who underwent curative resection for ampullary carcinoma during the ten-year period (1986-95) were reviewed. And, using paraffin-embedded tumor tissues, immunohistochemical (IHC) staining for p53, c-erbB-2, CgA, and PCNA was performed.
RESULTS
The overall five-year survival rate (5-YSR) for these 96 patients was 58%. With regard to TNM stage, the 5-YSR was 71% for stage I (n=36), 62% for stage II (n=29), and 39% for stage III (n=31), respectively. IHC expression rate was 17.6% for c-erbB-2, 19.2% for CgA, and 42.9% for p53. The relative proportion of labelling index of PCNA (<25%, 25-50%, >50%) was 30.8%, 25.3%, and 44.0%, respectively. The PCNA labelling index showedsignificant correlation with tumor size (p=0.032). The PCNA labelling index, c-erbB-2, CgA and p53 were not correlated to extent of invasion, lymph node metastasis, stage, or histologic type. CgA and c-erbB-2 expression and the PCNA labelling index thus had no prognostic value. With regard to p53, the 5-YSR of p53 negative cases was 68.6%; that of p53 positive cases was 47%, with significant difference (p=0.038).
CONCLUSION
This result suggests that p53 expression is related to poor prognosis of ampullary carcinoma, and that c-erbB-2 and CgA expression, and the PCNA labelling index, are not significant prognostic factors.

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Expression of Cell Cycle Regulatory and Apoptosis-related Proteins in Etoposide-treated Human Skin Fibroblast: Jae We Cho, Min Ho Suh; J Korean Cancer Assoc. 2001;33(1):77-83.

Abstract PDF: PURPOSE
This study was designed to investigate effect of the etoposide on expression of cell cycle regulatory proteins and apoptosis-related proteins in human skin fibroblast (HSF).
MATERIALS AND METHODS
HSF cells were treated with etoposide. After treatment, expression patterns of cell cycle regulatory proteins and apoptosis-related proteins were analyzed by using Immunoprecipitation-Western blot method and RT-PCR.
RESULTS
Immediately after etoposide treatment, E2F-1 was up- regulated following MDM2 down-regulation. After E2F-1 up-regulation, p53 and p21WAF1 level was markedly increased without or with mRNA up-regulation, respectively. Consistent with these results, cell cycles arrested in mainly G1 phase 24 hr after etoposide treatment. However, HSF cells progressed into apoptosis 72 hr after etoposide treatment. In this process, caspase-3 activation and Bax up-regulation were observed.
CONCLUSION
In early response of etoposide treatment, E2F-1 plays an important role in p53 accumulation through MDM2 down- regulation. The increased p53 induce an increase of p21WAF1 level through p21WAF1 mRNA up-regulation. However, after long term treatment of etoposide, HSF cells resulted in apoptotic cell death through caspase-3 activation and Bax up-regulation.

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