Cancer Research and Treatment

Original Articles

Lymphoma

Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation: Ji Hae Nahm, Woo Ick Yang, Sun Och Yoon; Cancer Res Treat. 2020;52(4):1273-1282. Published online July 3, 2020; DOI: https://doi.org/10.4143/crt.2020.032

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Purpose
Forkhead box C1 (FOXC1) is critical for maintaining bone marrow microenvironments during hematopoiesis, but its role in hematological malignancies remains obscure. Here, we investigated whether FOXC1 regulates tumor dormancy and activation in the microenvironments of T and natural killer (NK) cell lymphomas.
Materials and Methods
One hundred and twenty cases of T and NK cell lymphomas were included; the immunohistochemical expression of FOXC1 was investigated in stromal cells, and numbers of FOXC1⁺ stromal cells were counted. Furthermore, the expression of phosphorylated p38 (p-p38) and phosphorylated ERK1/2 (p-ERK1/2) in tumor cells was investigated using immunohistochemistry.
Results
FOXC1 was variably expressed in C-X-C motif chemokine 12–associated reticular stromal cells, histiocytes, (myo)fibroblasts, and endothelial cells. The phenotypes of cases were categorized as dormant (high p-p38/low p-ERK1/2; n=30, 25.0%), active (high p-ERK1/2/low p-p38; n=25, 20.8%), or intermediate (others; n=65, 54.2%). Lower FOXC1⁺ stromal cell infiltration was associated with the dormant phenotype, the precursor T lymphoblastic leukemia/lymphoma subtype, and inferior overall survival rates, whereas higher FOXC1⁺ stromal cell infiltration was associated with the active phenotype and favorable patient prognosis (p < 0.05 for all).
Conclusion
These results suggested that FOXC1⁺ stromal cells within the microenvironments of T and NK cell lymphomas might be related to tumor phenotypes.

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Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells
Rintaro Ohe
Journal of Clinical and Experimental Hematopathology.2024; 64(3): 166. CrossRef

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Low Doses of Nonylphenol Promote Growth of Colon Cancer Cells through Activation of ERK1/2 via G Protein‒Coupled Receptor 30: Ming Xie, Jin-Long Liang, Han-Dong Huang, Mai-Jian Wang, Tao Zhang, Xue-Feng Yang; Cancer Res Treat. 2019;51(4):1620-1631. Published online May 15, 2019; DOI: https://doi.org/10.4143/crt.2018.340

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Purpose
Nonylphenol (NP) is an endocrine disruptor found in products such as cleaners, plastics, and detergents. It exerts actions similar to endogenous 17β-estradiol (E2) and is reported to influence various cancers. However, its role in colon cancer remains elusive.
Materials and Methods
Colon cancer cell lines COLO 205 and SW480 were employed in our study. The cells were treated with NP or E2 followed by measurement of apoptosis and proliferation using flow cytometry and MTT assays, respectively. G protein–coupled estrogen receptor 30 (GPR30) expression was visualized using immunofluorescence and Western blot. To investigate the underlying mechanism, the expression levels of GPR30, p-protein kinase A (PKA), c-myc, cyclin D1, and ERK1/2 were analyzed using Western blot. Meanwhile, the GPR30 antagonist G15 was utilized to validate the role of GPR30 in colon cancer progression. Finally, the effect of a GPR30 inhibitor on tumor growth was determined in vivo using tumor xenograft mouse models.
Results
NP facilitated the proliferation of colon cancer cells and induced apoptosis failure in vitro. Western blot revealed increased GPR30 expression levels in response to NP treatment. Cyclin D1, p-PKA, c-myc, and proliferating cell nuclear antigen, proteins that regulate the cell cycle, were all upregulated by NP, and NP-mediated ERK1/2 activation and subsequent cell proliferation were abrogated by the GPR30 inhibitor G15. Moreover, colon cancer mice that received G15 administration demonstrated impaired tumor growth in vivo.
Conclusion
Low dose NP promotes the growth of colon tumors through GPR30-mediated activation of ERK1/2 signaling.

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Nonylphenol promotes epithelial-mesenchymal transition in colorectal cancer cells by upregulating miR-151a-3p
Biao Wang, Nianjie Zhang, Lin Dai, Yuanwei Zhang, Shuo Yin, Xuefeng Yang
Discover Oncology.2025;[Epub] CrossRef
The role of di-(2-ethylhexyl) phthalate in cancer initiation and progression: Mechanisms and health implications
Xinrui Zhou, Wei Ye, Jiapeng Xu, Qiting Luo, Yuanyuan Huang, Jieyu Li, Qinchang Zhu, Ge Liu
Science of The Total Environment.2025; 959: 178285. CrossRef
HSV-1 inhibits melanogenesis of PIG1 cells through downregulation of VN1R5/ERK pathway
Yuxin Feng, Shibin Jiang, Jinping Yuan, Kun Zhou, Yansong Lu, Fenglin Zhuo, Xing-Hua Gao, Hong-Duo Chen, Rui-Qun Qi, Yan Wu
Archives of Dermatological Research.2025;[Epub] CrossRef
GPR30 Inhibits Neuronal Apoptosis After Subarachnoid Hemorrhage by Activating the Wnt/β-Catenin Pathway in a m6A-dependent Manner
Jun Peng, Jun He, Xiqi Hu, Ying Xia
Molecular Neurobiology.2025;[Epub] CrossRef
Differences in the role of Gper1 in colorectal cancer progression depending on sex
Iveta Herichová, Richard Reis, Denisa Vanátová
Oncology Letters.2025; 29(6): 1. CrossRef
Role of sex steroids in colorectal cancer: pathomechanisms and medical applications
Jianglan Wu
American Journal of Cancer Research.2024; 14(7): 3200. CrossRef
17β-estradiol in colorectal cancer: friend or foe?
Zihong Wu, Chong Xiao, Jiamei Wang, Min Zhou, Fengming You, Xueke Li
Cell Communication and Signaling.2024;[Epub] CrossRef
Magnetic nanoparticles for eliminating endocrine-disrupting compounds in water treatment – a quantitative systematic analysis
Juliana Guimarães, Igor Taveira, Thuane Mendes Anacleto, Alex Enrich-Prast, Fernanda Abreu
Frontiers in Environmental Science.2024;[Epub] CrossRef
Implications of estrogen and its receptors in colorectal carcinoma
Plabon Kumar Das, Joti Saha, Suja Pillai, Alfred K.‐Y. Lam, Vinod Gopalan, Farhadul Islam
Cancer Medicine.2023; 12(4): 4367. CrossRef
Endocrine-Disrupting Chemicals and Disease Endpoints
Changhwan Ahn, Eui-Bae Jeung
International Journal of Molecular Sciences.2023; 24(6): 5342. CrossRef
Hsp27, a potential EcR target, protects nonylphenol-induced cellular and organismal toxicity in Drosophila melanogaster
Shiwangi Dwivedi, Leonard Clinton D'Souza, Nidhi Ganesh Shetty, Shamprasad Varija Raghu, Anurag Sharma
Environmental Pollution.2022; 293: 118484. CrossRef
Effect of nonylphenol on the colonic mucosa in rats and intervention with zinc-selenium green tea (Camellia sinensis)
Shixu Li, Mucong Zheng, Xuefeng Yang, Jianling Zhang, Jie Xu, Jie Yu
Toxicology Research.2022; 11(1): 122. CrossRef
Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer
Tao Zhang, Wei-Wei Ning, Jie Zhang, Fu-Jian Xu, Xing-Qin Wang, Zheng-Biao Li, Ming Xie
Toxicology and Applied Pharmacology.2022; 436: 115854. CrossRef
Effects of subchronic exposure of nonylphenol on the expression of immune-related factors and estrogen receptors in the spleen of rats
Xiangjun Fu, Jie Xu, Chengyu Ni, Degang Yu, Haibo Wang, Pan Wang, Man Luo, Jie Yu
Environmental Sciences Europe.2022;[Epub] CrossRef
Mechanism of nonylphenol induced gastric inflammation through NF-κB/NLRP3 signaling pathway
Jie Xu, Shixu Li, Xuefeng Yang, Haibo Wang, Lina Ma, Yuan Shen, Jie Yu
Toxicology.2022; 479: 153294. CrossRef
Nonylphenol Promoted Epithelial–Mesenchymal Transition in Colorectal Cancer Cells by Upregulating the Expression of Regulator of Cell Cycle
Nian-jie Zhang, Yuanwei Zhang, Shuo Yin, Du-ji Ruan, Nian He, Xu Chen, Xue-feng Yang
Chemical Research in Toxicology.2022; 35(9): 1533. CrossRef
Co-exposure to BPA and DEHP enhances susceptibility of mammary tumors via up-regulating Esr1/HDAC6 pathway in female rats
Xuan Zhang, Cheng Cheng, Guopei Zhang, Mingyang Xiao, Liuli Li, Shengwen Wu, Xiaobo Lu
Ecotoxicology and Environmental Safety.2021; 221: 112453. CrossRef
Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2
Jing Wang, Yuan-wei Zhang, Nian-jie Zhang, Shuo Yin, Du-ji Ruan, Nian He, Xu Chen, Xue-feng Yang
Frontiers in Cell and Developmental Biology.2021;[Epub] CrossRef
Residential proximity to industrial pollution sources and colorectal cancer risk: A multicase-control study (MCC-Spain)
Javier García-Pérez, Nerea Fernández de Larrea-Baz, Virginia Lope, Antonio J. Molina, Cristina O'Callaghan-Gordo, María Henar Alonso, Marta María Rodríguez-Suárez, Benito Mirón-Pozo, Juan Alguacil, Inés Gómez-Acebo, Nieves Ascunce, Mercedes Vanaclocha-Esp
Environment International.2020; 144: 106055. CrossRef

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Invasion-Metastasis by Hepatocyte Growth Factor/c-Met Signaling Concomitant with Induction of Urokinase Plasminogen Activator in Human Pancreatic Cancer: Role as Therapeutic Target: Kyung Hee Lee, Myung Soo Hyun, Jae Ryong Kim; Cancer Res Treat. 2003;35(3):207-212. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.207

Abstract PDF

PURPOSE
Increased expression of the hepatocytes growth factor (HGF) receptor (c-Met) and urokinase type plasminogen activator (uPA) correlate with the development and metastasis of cancers. However, the mechanisms by which HGF/c-Met signaling mediate cancer progression and metastasis are unclear. Therefore, we investigated the roles of HGF/c-Met in tumor progression and metastasis in pancreatic cancer cell lines, L3.6PL and IMIN-PC2. MATERIALS AND METHODS: To see the functional c-Met protein, we were performed immunoprecipitation for functional c-Met protein. And also performed western bolot analysis and gel zymography for the functional uPA protein. To see the inhibition effects of uPAR monoclonal antibody on invasiveness of two pancreatic cancer cell lines, we were carried out standard two chamber invasion assay. RESULTS: At first, we observed the HGF-mediated c-Met phosphorylation and cell growth. c-Met phosphorylation was increased in the HGF-treated cells in a dose dependent manner. HGF resulted in increments of cell growth and ERK phosphorylation. HGF treatment increased the uPA expression and the uPA activity. A monoclonal antibody 3936, specific to uPAR receptor, inhibited HGF- mediated tumor cell invasion in a dose dependent manner.
CONCLUSION
These results suggest that functional c- Met and HGF/c-Met signaling up-regulate the activity of uPA and result in increments of invasion-metastasis in the pancreatic cancer cells.

Citations

Citations to this article as recorded by

PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells
He Xu, Di Wu, Mingming Xiao, Yubin Lei, Yalan Lei, Xianjun Yu, Si Shi
Science Advances.2024;[Epub] CrossRef
Reactive oxygen species regulate the generation of urokinase plasminogen activator in human hepatoma cells via MAPK pathways after treatment with hepatocyte growth factor
Kyung Hee Lee, Jae-Ryong Kim
Experimental and Molecular Medicine.2009; 41(3): 180. CrossRef
Reactive oxygen species regulate urokinase plasminogen activator expression and cell invasion via mitogen-activated protein kinase pathways after treatment with hepatocyte growth factor in stomach cancer cells
Kyung Hee Lee, Sang Woon Kim, Jae-Ryong Kim
Journal of Experimental & Clinical Cancer Research.2009;[Epub] CrossRef
Cellular Mechanisms of Hepatocyte Growth Factor-Mediated Urokinase Plasminogen Activator Secretion by MAPK Signaling in Hepatocellular Carcinoma
Kyung Hee Lee, Eun Young Choi, Myung Soo Hyun, Jong Ryul Eun, Byung Ik Jang, Tae Nyeun Kim, Heon Ju Lee, Dong Shik Lee, Sung Su Yun, Hong Jīn Kim, Jung Hye Kim, Jae-Ryong Kim
Tumori Journal.2008; 94(4): 523. CrossRef
Association of Extracellular Cleavage of E-Cadherin Mediated by MMP-7 with HGF-Induced in vitro Invasion in Human Stomach Cancer Cells
K.H. Lee, E.Y. Choi, M.S. Hyun, B.I. Jang, T.N. Kim, S.W. Kim, S.K. Song, J.H. Kim, J.-R. Kim
European Surgical Research.2007; 39(4): 208. CrossRef
Hepatocyte Growth Factor/c-Met Signaling in Regulating Urokinase Plasminogen Activator in Human Stomach Cancer: A Potential Therapeutic Target for Human Stomach Cancer
Kyung Hee Lee, Eun Young Choi, Myung Soo Hyun, Byung Ik Jang, Tae Nyeun Kim, Sang Woon Kim, Sun Kyo Song, Jung Hye Kim, Jae-Ryong Kim
The Korean Journal of Internal Medicine.2006; 21(1): 20. CrossRef
Expression of E-Cadherin and uPA and their Association with the Prognosis of Pancreatic Cancer
Sang Joon Shin, Kyeong Ok Kim, Min Kyoung Kim, Kyung Hee Lee, Myung Soo Hyun, Keuk Jun Kim, Joon Hyuk Choi, Hong Seok Song
Japanese Journal of Clinical Oncology.2005; 35(6): 342. CrossRef

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Radiation-induced Apoptotic Signaling Pathway in HL - 60 Cells: Sung Ja Ahn, Rae Kil Park, Sang Rock Lee, Woong Ki Chung, Byung Sik Nah, Taek Keun Nam, Hun Taeg Chung, Sun Rock Moon, Heoung Keun Kang, Seung Jin Park; J Korean Cancer Assoc. 2000;32(1):156-167.

Abstract PDF: PURPOSE
The mechanical insights of death of cancer cells by ionizing radiation are not yet clearly defined. Recent evidences have demonstrated that radiation therapy may induce cell death via activation of signaling pathway for apoptosis in target cells. This study was designed whether ionizing radiation may activate the signaling cascades of apoptosis including caspase family cystein proteases, mitogen-activated protein (MAP) kinases, and transcriptional activation factors in target cells eventually leading to death.
MATERIALS AND METHODS
HL-60 cell line in the log phase was used in this study and the culture media was RPMI 1640. The irradiation was done using the linear accelarator and the radiation does was 10 Gy, 20 Gy, and 30 Gy, respectively. The cell viability was tested by MTT assay and apoptosis was identified by the DNA fragmentation assay. JNK1 (cJun N-terminal kinase) and ERK (extracellular-signal regulated protein kinase) activity was analyzed by the in vitro Ig complex kinase assay. NF- kB (Nuclear Factor- kB) and AP-1 (activator protein-1) activity was assayed by the electrophoretic mobility sbift assay.
RESULTS
Ionizing radiation decreased the viability of HL-60 cells in a time and dose dependent manner. Ionizing radiation-induced cell death of HL-60 cells may be an apo- ptotic death which was evidenced as apoptotic characteristic ladder pattern fragmentation of DNA over 20 Gy at 4 hours. Ionizing radiation specifically induced the activation of CPP32-like cystein protease rather than ICE-like protease of HL-60 cells in a time and dose dependent manner. The activation of CPP32-like cystein protease was also evidenced by the digestion of poly (ADP-ribose) polymerase with 30 Gy ionizing irradiation at 2 hours. The activity of JNK1 was transiently increased up to 3.6 fold by 30 Gy ionizing radiation at 2 hours. Ionizing radiation also rapidly activated the transcriptional activation factors including AP-1 and NF- kB at 10 or 30 min.
CONCLUSION
These data suggested that ionizing radiation-induced apoptosis was mediated by the activation of CPP32-like cystein protease, JNK1, and transcriptional activation factors

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