Cancer Research and Treatment

Original Articles

Prognostic Role of Rb, p16, Cyclin D1 Proteins in Soft Tissue Sarcomas: Byoung Yong Shim, Jinyoung Yoo, Yeon-Soo Lee, Young Sun Hong, Hoon-Kyo Kim, Jin-Hyoung Kang; Cancer Res Treat. 2010;42(3):144-150. Published online September 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.3.144

Purpose

The aim of this study was to determine the expressions of Rb, p16, and cyclin D1 in soft tissue sarcomas, and we also wanted to identify the prognostic factors according to the clinicalpathologic features.

Materials and Methods

We reviewed the charts and radiographic films of 66 sarcoma patients. Tissue samples were collected from these patients. Immunochemistry was performed using formalin-fixed, paraffin-embedded tissue samples to examine the expressions of p16, Rb, and cyclin D1 proteins.

Results

The median duration of overall survival was 47.8 months (range, 20.0 to 70.7 months) and the 5 years survival rate was 39%. As for the correlation between the degree of immunohistochemical staining for Rb protein and the histological tumor grades, there was a significant difference with a p-value of 0.019. However, no significant correlation was shown for p16 and cyclin D1. The overall survival duration of the Rb negative group (staining cell <20%) and the heterogeneous group (cell staining 20 to 80%) was 53.5±6.6 months and the overall survival duration of the Rb homogeneous group was 18.3±6.4 months, and there was a significant difference with a p-value of 0.016. However, no significant difference was shown between the survival rate according to the p16 and cyclin D1 expressions. On the multivariate analysis that was done with Rb, p16, the tumor size, grade and site, and patient age, the Rb gene expression was the most significant independent prognostic factor with a risk ratio of 3.01 (p=0.04).

Conclusion

The expression of Rb protein was correlated with the histologic grade and overall survival of patients with soft tissue sarcomas.

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Immunohistochemical Expression of p16 and CDK4 in Soft Tissue Tumors
Mala Sagar, Rita Yadav, Pankaj Deval, Madhu Kumar, Malti K Maurya, Sumaira Qayoom
Cureus.2023;[Epub] CrossRef
Carcinosarcoma, a Rare Malignant Neoplasm of the Pancreas
Jaffar Khan, Liang Cheng, Michael G. House, Shunhua Guo
Current Oncology.2021; 28(6): 5295. CrossRef
Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology
Yu Jin Kim, Mingi Kim, Hyung Kyu Park, Dan Bi Yu, Kyungsoo Jung, Kyoung Song, Yoon-La Choi
Laboratory Investigation.2019; 99(9): 1309. CrossRef
Prognostic significance of p16INK4a alteration in soft tissue sarcomas: A meta-analysis
Gang Lin, Yue Lou
Indian Journal of Cancer.2017; 54(3): 580. CrossRef
GATA3 Expression Is a Poor Prognostic Factor in Soft Tissue Sarcomas
Toshiaki Haraguchi, Hiroaki Miyoshi, Koji Hiraoka, Shintaro Yokoyama, Yukinao Ishibashi, Toshihiro Hashiguchi, Koutaro Matsuda, Tetsuya Hamada, Takahiro Okawa, Naoto Shiba, Koichi Ohshima, Ichiro Aoki
PLOS ONE.2016; 11(6): e0156524. CrossRef
Sarcoma spreads primarily through the vascular system: are there biomarkers associated with vascular spread?
Elisabetta Pennacchioli, Giulio Tosti, Massimo Barberis, Tommaso M. De Pas, Francesco Verrecchia, Claudia Menicanti, Alessandro Testori, Giovanni Mazzarol
Clinical & Experimental Metastasis.2012; 29(7): 757. CrossRef

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The Keratin-14 Expression in Actinic Keratosis and Squamous Cell Carcinoma: Is This a Prognostic Factor for Tumor Progression?: Kwang Hyun Choi, Gyong Moon Kim, Si Yong Kim; Cancer Res Treat. 2010;42(2):107-114. Published online June 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.2.107

Abstract PDF PubReader ePub

Purpose

Actinic keratosis (AK) is an incipient form of cutaneous squamous cell carcinoma (SCC). We determined if the pattern of expression of keratin-14 (K14) is a factor for tumor progression in AK and SCC.

Materials and Methods

Eighteen sections from the tissues of 16 patients were stained with anti-K14 antibody and p16^INK4a. Among the 16 patients, 4 were diagnosed with both SCC and AK at the same site, but AK developed first and SCC developed subsequently. Thus, SCC may have evolved from AK. The other 12 patients were only diagnosed with AK.

Results

In all of the AK and SCC tissues, basement membranes showed positive staining for K14. However, strong reactivities were shown in the spinous and granular layers and focuses of dermal invasion in the SCC tissues developed from AK. Two and 3 of the 12 AK cases had moderately positive reactions for K14 in the spinous and granular layers, respectively. Also, all SCC tissues except one had moderate-to-strong reactions in the basal, spinous, and granular layers for p16^INK4a. Two of the 12 AK cases had weak-to-moderate positive reactions in the basal, spinous, and horny layers for p16^INK4a.

Conclusion

The results of our study advance our understanding of the pathogenesis of SCC developing from AK. The results also indicate a differential role in the control of K14 in normal epithelia, AK, and SCC. K14 expression in the spinous and granular layers may be a prognostic factor for tumor progression of AK.

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Ex Vivo Analysis of Cell Differentiation, Oxidative Stress, Inflammation, and DNA Damage on Cutaneous Field Cancerization
Lara Camillo, Elisa Zavattaro, Federica Veronese, Laura Cristina Gironi, Ottavio Cremona, Paola Savoia
International Journal of Molecular Sciences.2024; 25(11): 5775. CrossRef
Enhanced Metastatic Risk Assessment in Cutaneous Squamous Cell Carcinoma with the 40-Gene Expression Profile Test
Sherrif F Ibrahim, Julia M Kasprzak, Mary A Hall, Alison L Fitzgerald, Jennifer J Siegel, Sarah J Kurley, Kyle R Covington, Matthew S Goldberg, Aaron S Farberg, Shannon C Trotter, Kenneth Reed, David G Brodland, Shlomo A Koyfman, Ally-Khan Somani, Sarah T
Future Oncology.2022; 18(7): 833. CrossRef
Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma
Ashley Wysong, Jason G. Newman, Kyle R. Covington, Sarah J. Kurley, Sherrif F. Ibrahim, Aaron S. Farberg, Anna Bar, Nathan J. Cleaver, Ally-Khan Somani, David Panther, David G. Brodland, John Zitelli, Jennifer Toyohara, Ian A. Maher, Yang Xia, Kristin Bib
Journal of the American Academy of Dermatology.2021; 84(2): 361. CrossRef
Expression Profile of Fibroblast Growth Factor Receptors, Keratinocyte Differentiation Markers, and Epithelial Mesenchymal Transition-Related Genes in Actinic Keratosis: A Possible Predictive Factor for Malignant Progression?
Flavia Persechino, Danilo Ranieri, Luisa Guttieri, Monica Nanni, Maria Rosaria Torrisi, Francesca Belleudi
Biology.2021; 10(4): 331. CrossRef
Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/β-Catenin Signaling Pathway
Gink N. Yang, Xanthe L. Strudwick, Claudine S. Bonder, Zlatko Kopecki, Allison J. Cowin
International Journal of Molecular Sciences.2021; 22(24): 13203. CrossRef
Equine Hoof Canker: Bovine Papillomavirus Infection Is Not Associated With Impaired Keratinocyte Differentiation
Veronika Apprich, Theresia Licka, Sabrina Freiler, Cordula Gabriel
Veterinary Pathology.2020; 57(4): 525. CrossRef
Keratin 14-high subpopulation mediates lung cancer metastasis potentially through Gkn1 upregulation
Shun Yao, Hsin-Yi Huang, Xiangkun Han, Yi Ye, Zhen Qin, Gaoxiang Zhao, Fuming Li, Guohong Hu, Liang Hu, Hongbin Ji
Oncogene.2019; 38(36): 6354. CrossRef
Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin
Manuel Rodríguez-Paredes, Felix Bormann, Günter Raddatz, Julian Gutekunst, Carlota Lucena-Porcel, Florian Köhler, Elisabeth Wurzer, Katrin Schmidt, Stefan Gallinat, Horst Wenck, Joachim Röwert-Huber, Evgeniya Denisova, Lars Feuerbach, Jeongbin Park, Bened
Nature Communications.2018;[Epub] CrossRef
Phenotypic characterization of oral mucosa: what is normal?
Jaroslav Valach, René Foltán, Marek Vlk, Pavol Szabo, Karel Smetana
Journal of Oral Pathology & Medicine.2017; 46(9): 834. CrossRef
A Mouse Model of Hyperproliferative Human Epithelium Validated by Keratin Profiling Shows an Aberrant Cytoskeletal Response to Injury
Samal Zhussupbekova, Rohit Sinha, Paula Kuo, Paul F. Lambert, Ian H. Frazer, Zewen K. Tuong
EBioMedicine.2016; 9: 314. CrossRef
Cutaneous Squamous Cell Carcinomas of the Lower Extremities Show Distinct Clinical and Pathologic Features
Jason F. Solus, George F. Murphy, Stefan Kraft
International Journal of Surgical Pathology.2016; 24(1): 29. CrossRef
Coordinate expression of cytokeratins 7 and 14, vimentin, and Bcl-2 in canine cutaneous epithelial tumors and cysts
Jason B. Pieper, Adam W. Stern, Suzette M. LeClerc, Karen L. Campbell
Journal of Veterinary Diagnostic Investigation.2015; 27(4): 497. CrossRef
The influence of the location of the lesion on the absolute risk of the development of skin cancer in a patient with actinic keratosis
P. Smit, E. Plomp, H.A.M. Neumann, H.B. Thio
Journal of the European Academy of Dermatology and Venereology.2013; 27(6): 667. CrossRef
Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells
Hunain Alam, Lalit Sehgal, Samrat T. Kundu, Sorab N. Dalal, Milind M. Vaidya, Robert David Goldman
Molecular Biology of the Cell.2011; 22(21): 4068. CrossRef
A new approach for skin tumor treatment: from delivery system characterization to in vivo evaluation
Denize Ainbinder, Elka Touitou
Drug Delivery and Translational Research.2011; 1(1): 53. CrossRef

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Cyclin D1 Overexpression, p16 Loss, and pRb Inactivation Play a Key Role in Pulmonary Carcinogenesis and have a Prognostic Implication for the Long-term Survival in Non-small Cell Lung Carcinoma Patients: Na-Hye Myong; Cancer Res Treat. 2008;40(2):45-52. Published online June 30, 2008; DOI: https://doi.org/10.4143/crt.2008.40.2.45

Abstract PDF PubReader ePub

Purpose

We investigated the immunoexpressions of cyclin D1, cyclin-dependent kinase inhibitor p16 and phosphorylated retinoblastoma (p-pRb) proteins in non-small cell lung carcinoma (NSCLC) to demonstrate their key roles in tumorigenesis, their relationship with the clinicopathologic factors, and their prognostic influences on the long-term survival.

Materials and Methods

115 surgically resected NSCLCs were immunohistochemically stained for the G₁/S cell cycle proteins, with using a tissue microarray. The correlation between their immunoexpressions and the clinicopathologic prognostic factors, their inter-relationships and their single or combined effects on the long-term survival (over 5 years) were statistically analyzed by SPSS15.0.

Results

Loss of p16 was found in 75% of the cases and cyclin D1 overexpression and phosphorylated pRb (p-pRb) were found in 64% and 46%, respectively. Cyclin D1 overexpression was correlated with the p16 loss and pRb inactivation by phosphorylation. The p16 loss was tightly associated with p-pRb. The Kaplan-Meier survival curves disclosed that the cyclin D1-positive group and the p16-negative group showed a rapid decline of survival at the point of about 5 years after surgery and thereafter. The combined actions of cyclin D1 overexpression, loss of p16 and pRb inactivation tended to have an adverse influence on the prolonged survival.

Conclusions

The observation that cyclin D1 overexpression, p16 loss and pRb inactivation were largely found in NSCLCs suggests that they play an important role in pulmonary carcinogenesis. Also, their inverse or positive correlations indicate that the G₁/S cell cycle proteins may act alternatively or synergistically on the mechanisms by which tumor cells escape the G₁ restriction point. Finally, their solitary or combined actions might have a long-term effect on the survival.

Citations

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Human Papillomavirus Is Rare and Does Not Correlate with p16INK4A Expression in Non-Small-Cell Lung Cancer in a Jordanian Subpopulation
Ola Abu Al Karsaneh, Arwa Al Anber, Sahar AlMustafa, Hussien AlMa’aitah, Batool AlQadri, Abir Igbaria, Rama Tayem, Mustafa Khasawneh, Shaima Batayha, Tareq Saleh, Mohammad ALQudah, Maher Sughayer
Medicina.2024; 60(4): 660. CrossRef
RB1: governor of the cell cycle in health and disease—a primer for the practising pathologist
Fleur Cordier, David Creytens
Journal of Clinical Pathology.2024; 77(7): 435. CrossRef
The Intersection of Genetic and Molecular Biology in Oral Potentially Malignant Disorders: Identifying Key Biomarkers and Pathways for Clinical Intervention
Hema Shree K
International Journal of Histopathological Interpretation.2024; 13(2): 1. CrossRef
Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia
Shimeng Zhao, Zhiguang Chen, Shuang Han, Hongmin Wu
Experimental and Therapeutic Medicine.2021;[Epub] CrossRef
Co-Occurrence of Differentiated Thyroid Cancer and Second Primary Malignancy: Correlation with Expression Profiles of Mismatch Repair Protein and Cell Cycle Regulators
Chih-Yi Liu, Ching-Shui Huang, Chi-Cheng Huang, Wei-Chi Ku, Hsing-Yu Shih, Chi-Jung Huang
Cancers.2021; 13(21): 5486. CrossRef
Ultrasound-Targeted Microbubble Destruction Mediated si-CyclinD1 Inhibits the Development of Hepatocellular Carcinoma via Suppression of PI3K/AKT Signaling Pathway

Wei Yan, Li Cheng, Dongmei Zhang
Cancer Management and Research.2020; Volume 12: 10829. CrossRef
Loss of pRB in Conjunctival Squamous Cell Carcinoma: A Predictor of Poor Prognosis
Sheetal Chauhan, Seema Sen, Anjana Sharma, Seema Kashyap, Radhika Tandon, Neelam Pushker, Murugesan Vanathi, Shyam S. Chauhan
Applied Immunohistochemistry & Molecular Morphology.2018; 26(6): e70. CrossRef
Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways
Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
Revista Portuguesa de Pneumologia (English Edition).2015; 21(5): 259. CrossRef
Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression
Rita Nahta, Fahd Al-Mulla, Rabeah Al-Temaimi, Amedeo Amedei, Rafaela Andrade-Vieira, Sarah N. Bay, Dustin G. Brown, Gloria M. Calaf, Robert C. Castellino, Karine A. Cohen-Solal, Anna Maria Colacci, Nichola Cruickshanks, Paul Dent, Riccardo Di Fiore, Stefa
Carcinogenesis.2015; 36(Suppl 1): S2. CrossRef
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
William H. Goodson, Leroy Lowe, David O. Carpenter, Michael Gilbertson, Abdul Manaf Ali, Adela Lopez de Cerain Salsamendi, Ahmed Lasfar, Amancio Carnero, Amaya Azqueta, Amedeo Amedei, Amelia K. Charles, Andrew R. Collins, Andrew Ward, Anna C. Salzberg, An
Carcinogenesis.2015; 36(Suppl 1): S254. CrossRef
Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary
George Fotopoulos, Anna Gousia, Eleni Bareta, Epameinondas Koumpis, Sofia Chrisafi, Matthaios Bobos, Vassiliki Malamou‐Mitsi, George Fountzilas, Nicholas Pavlidis, George Pentheroudakis
European Journal of Clinical Investigation.2015; 45(11): 1145. CrossRef
WITHDRAWN: Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways
Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
Revista Portuguesa de Pneumologia.2014;[Epub] CrossRef
Association between cyclin D1 G870A polymorphism and cervical cancer risk: a cumulative meta-analysis involving 2,864 patients and 3,898 controls
Yuan-Yuan Hu, Rong Zheng, Chong Guo, Yu-Ming Niu
Diagnostic Pathology.2014;[Epub] CrossRef
Chordoma: the entity
Youssef Yakkioui, Jacobus J. van Overbeeke, Remco Santegoeds, Manon van Engeland, Yasin Temel
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2014; 1846(2): 655. CrossRef
RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis
Riccardo Di Fiore, Antonella D'Anneo, Giovanni Tesoriere, Renza Vento
Journal of Cellular Physiology.2013; 228(8): 1676. CrossRef
Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer
William Sterlacci, Michael Fiegl, Alexandar Tzankov
Pathobiology.2012; 79(4): 175. CrossRef
Expression of Cyclin D1 Is Associated with β-Catenin Expression and Correlates with Good Prognosis in Colorectal Adenocarcinoma
Kyu Yun Jang, Yo Na Kim, Jun Sang Bae, Myoung Ja Chung, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee, Ho Sung Park
Translational Oncology.2012; 5(5): 370. CrossRef
A Comprehensive Analysis of p16 Expression, Gene Status, and Promoter Hypermethylation In Surgically Resected Non-small Cell Lung Carcinomas
William Sterlacci, Alexandar Tzankov, Lothar Veits, Bettina Zelger, Michel P. Bihl, Anja Foerster, Florian Augustin, Michael Fiegl, Spasenija Savic
Journal of Thoracic Oncology.2011; 6(10): 1649. CrossRef
Expression of p16 in non-small cell lung cancer and its prognostic significance: A meta-analysis of published literatures
Jinlong Tong, Xinchen Sun, Hongyan Cheng, Di Zhao, Jun Ma, Qing Zhen, Yuandong Cao, Huiping Zhu, Jianling Bai
Lung Cancer.2011; 74(2): 155. CrossRef

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Detection of p16(INK4A) in the Mixed Cell Populations of Normal Peripheral Blood Mononuclear Cells and Cervical Cancer Cell Lines: Ji Young Kwon, Yoon Sung Jo, Ye Hoon Choi, Jong Gyu Chang, Ki Sung Ryu, Jong Gu Rha, Ku Taek Han; Cancer Res Treat. 2003;35(3):254-260. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.254

Abstract PDF

PURPOSE
Human papilloma viruses (HPVs) play a central role in the pathogenesis of neoplastic lesions of the uterine cervix. The viral oncoprotein HPV E6 degrades the p53 protein, and the HPV E7 protein inactivates pRB and increases the expression of the CDK inhibitor, p16(INK4A). We investigated the usefulness of p16(INK4A) as a biologic marker for the cervical dysplastic and neoplastic cells.
MATERIALS AND METHODS
We examined the expression of p16(INK4A) and cytokeratin in a mixed population of normal peripheral blood mononuclear cells (PBMC) and the cervical cancer cell lines (HeLa, SiHa, and CasKi) using flow cytometry. RESULTS: The DNA indices of the HeLa, SiHa and CasKi cell lines were 1.89, 1.53 and 1.75, respectively, indicating that these cells are aneuploid cells. Furthermore, the positive rate of p16(INK4A) expression was 86.7% for the HeLa mixed population, 85.6% for the SiHa mixed population, and 92.2% for the CasKi mixed population. According to the FL3A vs FL3W histogram, electrical gating of the HeLa, SiHa and CasKi mixed populations showed the expression levels of both cytokeratin and p16(INK4A) to be identical, at 86.6%, 84.8% and 85.0%, respectively. These findings revealed that almost all cells selected through electrical gating were cervical cancer cells originating from the epithelium and which expressed cytokeratin and p16(INK4A). On the other hand, when each mixed population was electrically gated for normal PBMC, we found that the PBMCs expressed neither cytokeratin nor p16(INK4A).
CONCLUSION
Using flow cytometry, we observed the enhanced expression of p16(INK4A) in cervical cancer cell lines. These RESULTS suggest the usefulness of p16(INK4A) for the selective detection of cervical dysplastic and cancer cells in the liquid-based samples, which are taken from the cervices and contaminated with blood and stromal cells.

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2-Methoxyestradiol: A Hormonal Metabolite Modulates Stimulated T-Cells Function and proliferation
J.G.Y. Luc, R. Paulin, J.Y. Zhao, D.H. Freed, E.D. Michelakis, J. Nagendran
Transplantation Proceedings.2015; 47(6): 2057. CrossRef

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Expression of G1/S Phase Checkpoint Proteins in Breast Carcinoma: Relationship to Clinicopathologic Factors andSurvival Rate: Mi Ja Lee; Cancer Res Treat. 2002;34(4):268-273. Published online August 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.4.268

Abstract PDF: The retinoblastoma protein (pRb)/cyclin D1/ p16 pathway plays a critical role in controlling the progression from G1 to S phase of the cell cycle. Abnormal expression of the individual components of the pathway has been reported in many human cancers, including the breast. Our aim was to investigate the role of this pathway in tumorigenesis and tumor progression, and to evaluate the value of these oncoproteins as potential prognostic factors in breast cancer.
MATERIALS AND METHODS
We examined the significance of the p16, pRb, and cyclin D1 expression in 128 cases of invasive breast carcinomas using immunohistochemistry on formalin fixed, paraffin sections. The results correlated with the survival rate and clinicopathologic variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER) and progesterone receptor (PR) content. The negative finding for nuclear staining for pRb and p16 were defined as abnormal.
RESULTS
Abnormal expression of the p16 and pRb were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between the p16 and pRb expressions. There was no association between the p16 staining and any other parameters, including survival rate, cyclin D1, or clinicopathologic variables. Surprisingly, there was a trend for pRb positive tumors to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grades, and with higher ER and PR expressions.
CONCLUSION
These findings suggest the p16 may be negatively regulated by the pRb, and that cyclin D1 is involved in the tumor progression in well-differentiated tumors and could be an ER and PR related protein. In a Cox multivariate analysis, the p16, pRb, and cyclin D1 were not independent predictors of patient outcome.

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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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Alterations of p15INK4B, p16INK4A and Methylthioadenosine Phosphorylase Gene in Korean Hepatdegrees Cellular Carcinoma: Ho Young Pyun, Jae We Cho, Won Ki Baik, Jong Wook Park, Jae Pok Park, Min Ho Suh, Seong Il Suh; J Korean Cancer Assoc. 2000;32(3):553-562.

Abstract PDF: PURPOSE
We analyzed the gene status of p16INK4A, p15INK4B and MTAP (methylthio adenosine phophorylase) in Korean hepatdegrees Cellular carcinoma (HCC) to investigate whether the inactivation of these genes participated in hepatdegrees Carcinogenesis, and evaluated MTAP-targeted chemotherapy in MTAP-deficient cell lines. MATERIAL AND METHODS: We examined eleven primary HCC and 8 SNU cell lines using PCR, Southern blot analysis, PCR-SSCP, DNA sequencing, methylation-specific PCR, Western blot analysis, MTT assay, and crystal violet staining.
RESULTS
Mutations or deletion of the p16INK4A, 15INK4B, and MTAP genes were rare, but methylation of the p16INK4A promoter region was common in HCC. The base alterations of 3' untranslated region of p16INK4A exon 3 were also detected in 3 samples. In SNU cells, p16INK4A was not detectable, when treated with demethylating agent, high levels of re-expressed p16INK4A protein were detected. In MTAP-targeted chemotherapy experiment, methylthioadeno sine (MTA) was able to rescue MTAP positive cell lines but not MTAP negative cell lines from growth inhibition by depletion of methionine and MTX treatment.
CONCLUSION
These results suggest that de novo methylation of the p16INK4A promoter region seems to play an important role in the pathogenesis of HCC. And treatment of MTX, combined with methionine depletion in the presence of MTA, may be a high selective treatment for MTAP negative HCC.

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Genetic Alterations of p16Ink4A and p15Ink4B in Gastric Carcinomas: Kwon Hur, Han Kwang Yang, Ja June Jang, Jin Pok Kim, Dae Young Kim; J Korean Cancer Assoc. 1999;31(5):887-897.

Abstract PDF: PURPOSE
p16Ink4A and p15lnk4B, encoded by the genes located on chromosome 9p21, are cyclin-dependent kinase 4 inhibitors and are the upstream regulators of pRB (retinoblastoma protein) function and are involved in the regulation of cell cycle in mammalian cells. It has been demonstrated that p16 and p15 genes are frequently deleted, mutated, and hypermethylated in many malignancies and cancer cell lines. This study was performed to investigate the genetic alteration and immunohistochemical profile of p16 and p15 in gastric carcinomas.
MATERIALS AND METHODS
We examined 30 primary gastric cancer samples using PCR- SSCP (Polymerase chain reaction-single strand conformation polymorphism), DNA sequencing, PCR-based hypermethylation assay, and immunohistochemistry.
RESULTS
No homozygous deletion was detected in either pl6 or p15 gene, and only one gastric carcinoma sample showed mutation of p16 gene and p15 gene. However, hyper-methylation of 5' CpG islands was observed in 53.6% of exon1 of p16 gene and in 46.4% of exon 1 of pl5 gene. By immunohistochemistry of p16, nuclear under-expression was observed in 58.6%, whereas nuclear over-expression was detected in 31% of formalin-fixed, paraffin-embedded gastric cancer tissues.
CONCLUSIONS
Our results suggest that the p16 and p15 tumor suppressor genes may play an important role in gastric carcinogenesis and may be inactivated not by deletions or mutations but mainly by hypermethylation of their 5' CpG islands. There was a good correlation between methylation study and immunohistochemical results in p16 genes.

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The p16INK4A Expression in Stomach Cancer , Colon Cancer and Hepatoma Cell Lines: Sun Ju Choi, Soo Kie Kim, Se Jong Kim, Choon Myung Koh, Yoon Sun Park; J Korean Cancer Assoc. 1998;30(3):527-535.

Abstract PDF: PURPOSE
The p16(INK4A) gene encodes a specific inhibitor of cell cycle progression. In recent years, genetic deletion and altered expression of p16(INK4A) gene were frequently showed in many human cancers. So, the p16(INK4A) gene is considered as tumor suppressor gene. However, there has been a few data for the p16(INK4A) in gastric cancer, colon cancer, and hepatoma.So.we investigated the genetic deldtion and altered expression of p16(INK4A) in gastric cancer, colon cancer and hepatoma cell lines.
MATERIALS AND METHODS
The homozygous deletion of p16(INK4A) was examined by using PCR and the protein expression of p16(INK4A) by using Western blotting in cancer cell lines established from Korean patients: stomach cancer, colon cancer and hepatoma cell lines.
RESULTS
Homozygous deletion of p16(INK4A) was detected only 1 stomach cancer cell line out of 13 cell lines examined. The p16(INK4A) was detected in 3 of 13 cancer cell line. These results showed the low frequency of p16(INK4A) homozygous deletion and high frequency of p16(INK4A) expression alteration in stomach cancer, colon cancer and hepatoma cell lines.
CONCLUSION
In this study, it may be suggested that the altered pl6(INK4A) expression as well as p16(INK4A) gene deletion play important role in oncogenesis. Further studies to determine the mechanism of p16(INK4A) gene inactivation are expected.

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