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SOCS3 gene silencing does not occur through methylation and mutations in gastric cancer. Hum Cell 2022; 35:1114-1125. [PMID: 35596898 DOI: 10.1007/s13577-022-00715-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/04/2022] [Indexed: 11/04/2022]
Abstract
Gastric cancer (GC) is ranked the third leading cause of cancer-related deaths worldwide. Mutations and epigenetic alterations in several essential genes, including p53, KRAS, PIK3CA, FAT4 and ARID1A, are often reported. Furthermore, loss of SOCS3 expression was reported in GC, suggesting its tumor suppressor role. To assess the mutational and methylation status of SOCS3, we performed gene panel exome sequencing on 47 human GC samples. The SOCS3 gene was rarely mutated, suggesting alternative regulation mechanisms, such as promoter hypermethylation and/or long non-coding RNAs (lncRNAs). We first explored SOCS3 promoter methylation status in 44 human GC samples by methylation-specific PCR (MS-PCR). Thirteen out of forty-four patients (29.5%) displayed a methylation pattern. Then, to see whether SOCS3 expression is silenced by CpG methylation, we examined publicly available databases (cbioportal and The Cancer Genome Atlas (TCGA)). The analysis revealed β values lower than 0.1, indicating hypo-methylation in healthy and GC samples. Moreover, moderate methylation (β < 0.4) and high methylation (β > 0.4) did not affect the free survival, suggesting that methylation is unlikely to be the mechanism ruling SOCS3 silencing in GC. Next, to assess the regulatory effects of lncRNAs on SOCS3, we silenced the AC125807.2-lncRNA and quantified the SOCS3 gene expression in AGS and NCI-N87 gastric cancer cell line. SOCS3 was found to be downregulated following AC125807.2-lncRNA silencing in AGS cells, suggesting the potential implication of lncRNA AC125807.2 in SOCS3 regulation. However, in NCI-N87 cells, there was no significant change in SOCS3 expression. In conclusion, neither mutations nor hypermethylation was associated with the SOCS3 downregulation in GC, and alternative mechanisms, including non-coding RNAs-mediated gene silencing, may be proposed.
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Zhu Y, Zhang H, Han X, Wang Z, Cui Y, Tian R, Wang Z, Han B, Tian J, Zhang F, Niu R. STAT3 mediated upregulation of C-MET signaling acts as a compensatory survival mechanism upon EGFR family inhibition in chemoresistant breast cancer cells. Cancer Lett 2021; 519:328-342. [PMID: 34348188 DOI: 10.1016/j.canlet.2021.07.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/10/2021] [Accepted: 07/28/2021] [Indexed: 11/17/2022]
Abstract
Chemotherapy remains the most common treatment for all types of breast cancer. Chemoresistance in tumors is still a major obstacle for treating late-stage breast cancer. In the process of acquiring resistance, tumor cells dynamically evolve to adapt to the challenge of anti-cancer drugs. Besides the upregulation of drug-pumps, signal pathways related to proliferation and survival undergo adaptive evolution. Thus, these drug-resistant cells are more conducive to proliferation, even in stressful conditions. Nevertheless, the detailed mechanism that drives cancer cells to sustain their proliferation ability is unclear. Herein, we reported that the upregulated C-MET signaling acts as a compensatory mechanism that sustains the proliferation of chemoresistant cells in which EGFR family signaling was attenuated. Both C-MET and EGFR family are essential for cell proliferation due to their activation of the STAT3 signaling. Different from other cell models in which C-MET interacts with and phosphorylates EGFR family members, our cell model showed no direct interaction between C-MET and EGFR family members. Therefore, C-MET and EGFR family signaling pathways function independently to sustain the proliferation of resistant cells. Moreover, chemoresistant cells have evolved a novel, STAT3-C-MET feed-forward loop that plays a vital role in sustaining cell proliferation. The activated STAT3 interacts with the MET gene promoter to upregulate its transcription. Most importantly, the combined inhibition of C-MET and EGFR family synergistically inhibits the proliferation of drug-resistant cells in vitro and in xenograft tumor models. This work provides a new strategy for treating drug-resistant breast cancer.
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Affiliation(s)
- Yuying Zhu
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - He Zhang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xingxing Han
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhiyong Wang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yanfen Cui
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Ran Tian
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhaosong Wang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Baoai Han
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jianfei Tian
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Fei Zhang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Ruifang Niu
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Gu ML, Zhou XX, Ren MT, Shi KD, Yu MS, Jiao WR, Wang YM, Zhong WX, Ji F. Blockage of ETS homologous factor inhibits the proliferation and invasion of gastric cancer cells through the c-Met pathway. World J Gastroenterol 2020; 26:7497-7512. [PMID: 33384550 PMCID: PMC7754554 DOI: 10.3748/wjg.v26.i47.7497] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/13/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.
AIM To investigate the role and mechanism of EHF in the occurrence and development of GC.
METHODS The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.
RESULTS The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).
CONCLUSION These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.
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Affiliation(s)
- Meng-Li Gu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Xin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Ting Ren
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ke-Da Shi
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Mo-Sang Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Rui Jiao
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ya-Mei Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, Zhejiang Province, China
| | - Wei-Xiang Zhong
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Chen L, Shi Y, Zhu X, Guo W, Zhang M, Che Y, Tang L, Yang X, You Q, Liu Z. IL‑10 secreted by cancer‑associated macrophages regulates proliferation and invasion in gastric cancer cells via c‑Met/STAT3 signaling. Oncol Rep 2019; 42:595-604. [PMID: 31233202 PMCID: PMC6610037 DOI: 10.3892/or.2019.7206] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of the most common types of human cancer, and it is additionally one of the leading causes of cancer-associated mortality worldwide. Previous studies have suggested that interleukin (IL)-10 may contribute to the pathogenesis of gastric cancer. However, the underlying mechanisms remain unclear. In the present study, it was observed that the expression of IL-10 was significantly upregulated in gastric tumor tissues and serum samples of patients with gastric cancer. Furthermore, IL-10 was increased in the cell culture supernatant of cancer-associated macrophages (CAMs). Treatment with cell culture supernatant from CAMs induced a significant increase in proliferation and migration, while it suppressed apoptosis, in MGC-803 and BGC-823 gastric cancer cells. Notably, application of an inhibitory IL-10 antibody partially blocked the cell culture supernatant of CAM-induced oncogenic effects. RNA-sequencing analysis was then performed to identify the differentially expressed genes in MGC-803 cells treated with IL-10. Based on the sequencing results and in vitro analysis, it was demonstrated that IL-10-induced carcinogenic behaviors in MGC-803 cells were potentially mediated by activation of the c-Met/STAT3 signaling pathway. In conclusion, the present results demonstrated that IL-10 secreted by CAMs may be involved in the pathogenesis of gastric cancer, suggesting that IL-10 may serve as a potential therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Ling Chen
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Yuntao Shi
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Xiaojuan Zhu
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiwei Guo
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Mingjiong Zhang
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Ying Che
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Lijuan Tang
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Xiaozhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Qiang You
- Department of Biotherapy, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Zheng Liu
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Gao X, Sun J, Huang C, Hu X, Jiang N, Lu C. RNAi-mediated silencing of NOX4 inhibited the invasion of gastric cancer cells through JAK2/STAT3 signaling. Am J Transl Res 2017; 9:4440-4449. [PMID: 29118906 PMCID: PMC5666053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/19/2017] [Indexed: 06/07/2023]
Abstract
NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase (NOX) family of enzymes and has been found abnormally expressed in human cancers. However, its role in gastric cancer (GC) is still unclear. In the current study, we reported that NOX4 expression levels were significantly up-regulated in GC tissues compared to normal tissues (P<0.0001). Higher NOX4 expression was significantly associated with poorer overall survival in GC patients. Silencing NOX4 in two NOX4 high expression GC cell lines, MGC-803 and BGC-823 cells, did not affect cell proliferation, while inhibited cell adhesion and cell invasion of GC cells. Furthermore, Gene set enrichment analysis (GSEA) results indicated that NOX4 expression was strongly associated with cell migration, epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. More interestingly, Interleukin-6 (IL-6) increased the invasion ability and activation of JAK2/STAT3 of MGC-803 and BGC-823 cells. Such effects were attenuated by NOX4 silencing. Overexpression of NOX4 in one NOX4 low expression GC cell line, SGC-7901 cells, significantly promoted cell invasion, which was impaired by treatment of JAK2 inhibitor, AG490. AG490 inhibited STAT3 activation in SW1990 cells. NOX4 may exert its function through JAK2/STAT3 pathway. In summary, the findings of this study indicate that NOX4 may promote the development of GC, potentially representing a novel prognostic marker for overall survival in GC.
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Affiliation(s)
- Xiang Gao
- Department of Biostatistics and Computational Biology, SKLG, School of Life Sciences, Fudan UniversityShanghai, China
- Genergy Bio-technology (Shanghai) Co., LTDRoom 4B, Building#3, No. 401 Caobao Rd, Xuhui District, Shanghai, China
| | - Jingping Sun
- The First People’s Hospital of Wujiang DistrictSuzhou, Jiangsu, China
| | - Chunyu Huang
- Genergy Bio-technology (Shanghai) Co., LTDRoom 4B, Building#3, No. 401 Caobao Rd, Xuhui District, Shanghai, China
| | - Xiaohua Hu
- Department of Biostatistics and Computational Biology, SKLG, School of Life Sciences, Fudan UniversityShanghai, China
| | - Ning Jiang
- Department of Biostatistics and Computational Biology, SKLG, School of Life Sciences, Fudan UniversityShanghai, China
| | - Chenqi Lu
- Department of Biostatistics and Computational Biology, SKLG, School of Life Sciences, Fudan UniversityShanghai, China
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Li W, Zhang H, Nie M, Tian Y, Chen X, Chen C, Chen H, Liu R. Ursolic acid derivative FZU-03,010 inhibits STAT3 and induces cell cycle arrest and apoptosis in renal and breast cancer cells. Acta Biochim Biophys Sin (Shanghai) 2017; 49:367-373. [PMID: 28338932 DOI: 10.1093/abbs/gmx012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Indexed: 12/25/2022] Open
Abstract
Advanced renal cell carcinoma and triple negative breast cancer (TNBC) are malignancies without effective therapeutics currently. Ursolic acid (UA) has been previously reported to have anti-cancer effects in multiple solid tumors. In order to develop more potent anti-cancer reagents, FZU-03,010 based on the chemical structure of UA were synthesized. The results demonstrated that, compared with UA, FZU-03,010 could suppress renal cancer cell 786-0 and TNBC cell HCC1806 cell viability more potently. Furthermore, FZU-03,010 could induce G1 cell cycle arrest and cell apoptosis more efficiently than UA. FZU-03,010 could also inhibit signal transducer and activator of transcription 3 activation, induce the expression of cell cycle-dependent kinase inhibitors (p21 and p27) and promote cell apoptosis. In conclusion, our results suggest that the UA derivative FZU-03,010 is more potent in inhibiting cancer cell survival, and FZU-03,010 has the potential to be developed as a therapeutic for renal cell cancers and TNBCs.
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Affiliation(s)
- Wei Li
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming 650032, China
- Medical College of Kunming University of Science and Technology, Kunming 650032, China
| | - Hongxiu Zhang
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming 650032, China
- Medical College of Kunming University of Science and Technology, Kunming 650032, China
| | - Mingxiu Nie
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming 650032, China
- Medical College of Kunming University of Science and Technology, Kunming 650032, China
| | - Yanlei Tian
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming 650032, China
- Yunnan University of Traditional Chinese Medicine, Kunming 650032, China
| | - Xu Chen
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming 650032, China
- Medical College of Kunming University of Science and Technology, Kunming 650032, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Haijun Chen
- College of Chemistry, Fuzhou University, Fuzhou 350116, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
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[STAT3 activation by hypoxia in in vitro models of cervix cancer and endothelial cells]. BIOMEDICA 2017; 37:119-130. [PMID: 28527256 DOI: 10.7705/biomedica.v37i2.3225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 06/20/2016] [Indexed: 12/30/2022]
Abstract
INTRODUCTION The biological behavior of cancer cells is influenced by the tumor microenvironment in which they develop. In this context, stressor stimuli such as hypoxia are considered critical for tumor development and therapeutic management. Cellular response to various stimuli is evidenced in the activation of intracellular signaling pathways such as JAK/STAT, which is one of the most important for its effects in differentiation and cell proliferation. OBJECTIVE To evaluate the condition of the JAK/STAT pathway through the expression/activation of the STAT3 protein in cervix cancer cells (HeLa) and endothelial cells (EA.hy926) subjected to hypoxia. MATERIAL AND METHODS Cell lines were subjected to physical (1% O2) or chemical (deferoxamine, DFO, 100 μM) hypoxia for 2, 6 and 24 hours. Changes in the expression and activation of STAT3, and its subcellular localization by indirect immunofluorescence, were determined by western blot. RESULTS Hypoxia was evidenced by the activation and translocation to the nucleus of HIF-1. Neither physical nor chemical hypoxia altered STAT3 expression, but it did affect its activation, as seen in its phosphorylation and translocation to the nucleus in the two models under study. CONCLUSIONS The present study highlights the importance of hypoxia as a stimulus that modifies the activation of the STAT3 protein in HeLa and EA.hy926 cells, which makes it an important factor in the design of therapeutic strategies against cancer.
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Sun Y, Guo BF, Xu LB, Zhong JT, Liu ZW, Liang H, Wen NY, Yun WJ, Zhang L, Zhao XJ. Stat3-siRNA inhibits the growth of gastric cancerin vitroandin vivo. Cell Biochem Funct 2015; 33:495-502. [DOI: 10.1002/cbf.3148] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Revised: 09/14/2015] [Accepted: 09/16/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Ying Sun
- Department of Plastic Surgery, the China- Japan Union Hospital; Jilin University; Changchun China
| | - Bao-feng Guo
- Department of Plastic Surgery, the China- Japan Union Hospital; Jilin University; Changchun China
| | - Li-bo Xu
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Jia-teng Zhong
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Zhe-wen Liu
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Hang Liang
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Nai-yan Wen
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Wen-jing Yun
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Ling Zhang
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
| | - Xue-jian Zhao
- Department of Pathophysiology, College of Basic Medicine Sciences; Jilin University; Changchun China
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Yan R, Lin F, Hu C, Tong S. Association between STAT3 polymorphisms and cancer risk: a meta-analysis. Mol Genet Genomics 2015; 290:2261-70. [PMID: 26063618 DOI: 10.1007/s00438-015-1074-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 05/28/2015] [Indexed: 01/05/2023]
Abstract
Five polymorphisms, rs2293152, rs4796793, rs12949918, rs6503695, rs744166, in the STAT3 gene have been implicated in susceptibility to cancer, but the results were inconclusive. The aim of this meta-analysis is to investigate the association between the five polymorphisms and cancer risk. All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Wanfang, VIP, and CNKI. Effect sizes of odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated by using a fixed- or random-effect model. A total of 15 articles were included. Overall, a significantly decreased risk was found for rs12949918 polymorphism (dominant model: OR = 0.83, 95 % CI: 0.75-0.91, recessive model: OR = 0.77, 95 % CI: 0.68-0.87, TC vs. TT: OR = 0.87, 95 % CI: 0.79-0.96, CC vs. TT: OR = 0.71, 95 % CI: 0.62-0.81), and for rs744166 polymorphism (recessive model: OR = 0.75, 95 % CI: 0.58-0.98; GG vs. AA: OR = 0.68, 95 % CI: 0.51-0.90), while there was no significant association for other three polymorphisms under all genetic models. In subgroup analysis by ethnicity, for rs12949918 polymorphism, similar results were detected among Caucasians, similarly, a significant decreased risk was observed in Asians under dominant and CC vs. TT model; for rs2293152 polymorphism, significant association was detected among Asians under recessive model. This meta-analysis suggests that the STAT3 rs12949918 and rs744166 polymorphisms, but not other three polymorphisms, may be an important protective factor for cancer.
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Affiliation(s)
- Ruicheng Yan
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
| | - Fusheng Lin
- Department of General Surgery, Zhongshan Hospital of Xiamen University, Xiamen, 361004, Fujian Province, People's Republic of China
| | - Chao Hu
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Shilun Tong
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
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Yang Y, Zhao Q, Cai Z, Cheng G, Chen M, Wang J, Zhong H. Fas Signaling Promotes Gastric Cancer Metastasis through STAT3-Dependent Upregulation of Fascin. PLoS One 2015; 10:e0125132. [PMID: 25992623 PMCID: PMC4436300 DOI: 10.1371/journal.pone.0125132] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 03/11/2015] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Fas signaling-activated signal transducers and activators of transcription 3 (STAT3) is required for Fascin upregulation. As an actin-bundling protein, Fascin can mediate gastric cancer (GC) cell migration. METHODS Gastric cancer AGS cells were treated with anti-Fas (5 μg/ml) for 2 h, in order to stimulate the activation of the Fas signaling. The in vitro migration of Fas signaling-activated AGS cells was assessed using Transwell chambers. The levels of Fascin and phosphorylated STAT3 were detected by Western blotting analyses. Nude mice were injected intravenously with AGS cells treated with anti-Fas or treated with STAT3 inhibitor without anti-Fas; tumor pulmonary metastases were measured. Fascin protein expression in tumor tissues was detected by immunohistochemistry. The Fas and Fascin mRNA levels in tumor tissues from patients with GC were measured by real-time PCR and their correlation was analyzed. RESULTS The activation of Fas signaling promoted cell migration and resulted in STAT3-dependent Fascin upregulation in AGS cells. STAT3 enhanced Fascin levels in vivo. Fascin was the mediator of Fas signaling-induced AGS cell migration in vitro and in vivo. Furthermore, there was a positive correlation between Fas and Fascin mRNA levels in tumor tissues from GC patients. CONCLUSIONS Fas signaling promotes GC metastasis through the STAT3/Fascin pathway, which may provide a new target for GC therapy.
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Affiliation(s)
- Yunshan Yang
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Qiyu Zhao
- Hepatobiliary & Pancreatic Intervention Center, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China
| | - Zhijian Cai
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Guoping Cheng
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Ming Chen
- Department of Otolaryngology, the Second Affiliated Hospital of School of Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Jiaoli Wang
- Department of Medical Oncology, Nanjing Medical University, Affiliated Hangzhou Hospital (Hangzhou First People’s Hospital), Hangzhou, 310006 People’s Republic of China
| | - Haijun Zhong
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
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11
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Zhang N, Li YX, Tao L, Yang L, Zhao J, Zhang WJ. Clinicopathological and prognostic significance of IL-11 and Survivin overexpression in gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:373-380. [DOI: 10.11569/wcjd.v23.i3.373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differential expression of interleukin-11 (IL-11) and Survivin in gastric cancer (GC) to understand their possible roles in carcinogenesis, progression and prognosis.
METHODS: Paraffin-embedded samples were obtained from 59 GC patients who underwent surgical operations at the First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, China, between January 1, 2004 and December 31, 2007. All of the patients were followed to April 1, 20014. The expression of IL-11 and Survivin was detected using tissue chip and immunohistochemistry.
RESULTS: The positive expression rate of IL-11 was 96.6% in GC tissues, significantly higher than that in adjacent normal tissues (88.1%; χ2 = 7.252, (P = 0.025). The positive expression rate of Survivin in GC tissues was also significantly higher than that in adjacent normal tissues (93.2% vs 72.9%, χ2 = 41.988, P < 0.001). In GC tissues, there was a positive correlation between IL-11 and Survivin expression (r = 0.442, P < 0.001), but no correlation was found in adjacent normal tissues (r = 0.103, (P = 0.438). The expression of IL-11 was correlated with higher clinical stage ((P = 0.002), while Survivin expression was correlated with lymph node metastasis and higher clinical stage ((P = 0.002, 0.028). Higher levels of IL-11 and Survivin were linked to poor prognosis in GC patients ((P = 0.004 and P < 0.001, respectively). Cox multi-factorial regression analysis demonstrated clinical stage being an independent factor predicting overall survival of GC patients ((P = 0.017).
CONCLUSION: Overexpression of IL-11 and Survivin correlates with poor prognosis of GC patients, and they may play a coordinated role in the development, progression and prognosis of GC.
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12
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Zhang X, Ni Z, Duan Z, Xin Z, Wang H, Tan J, Wang G, Li F. Overexpression of E2F mRNAs associated with gastric cancer progression identified by the transcription factor and miRNA co-regulatory network analysis. PLoS One 2015; 10:e0116979. [PMID: 25646628 PMCID: PMC4315469 DOI: 10.1371/journal.pone.0116979] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/17/2014] [Indexed: 12/19/2022] Open
Abstract
Gene expression is regulated at the transcription and translation levels; thus, both transcription factors (TFs) and microRNAs (miRNA) play roles in regulation of gene expression. This study profiled differentially expressed mRNAs and miRNAs in gastric cancer tissues to construct a TF and miRNA co-regulatory network in order to identify altered genes in gastric cancer progression. A total of 70 cases gastric cancer and paired adjacent normal tissues were subjected to cDNA and miRNA microarray analyses. We obtained 887 up-regulated and 93 down-regulated genes and 41 down-regulated and 4 up-regulated miRNAs in gastric cancer tissues. Using the Transcriptional Regulatory Element Database, we obtained 105 genes that are regulated by the E2F family of genes and using Targetscan, miRanda, miRDB and miRWalk tools, we predicted potential targeting genes of these 45 miRNAs. We then built up the E2F-related TF and miRNA co-regulatory gene network and identified 9 hub-genes. Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation. These data showed Overexpression of E2F mRNAs associated with gastric cancer progression.
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Affiliation(s)
- XiaoTian Zhang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZhaoHui Ni
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZiPeng Duan
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZhuoYuan Xin
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - HuaiDong Wang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - JiaYi Tan
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - GuoQing Wang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
- * E-mail: (GW); (FL)
| | - Fan Li
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
- * E-mail: (GW); (FL)
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13
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Aoyagi K, Kouhuji K, Kizaki J, Isobe T, Hashimoto K, Shirouzu K. Molecular targeting to treat gastric cancer. World J Gastroenterol 2014; 20:13741-55. [PMID: 25320512 PMCID: PMC4194558 DOI: 10.3748/wjg.v20.i38.13741] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/13/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.
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14
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Ruzzo A, Catalano V, Canestrari E, Giacomini E, Santini D, Tonini G, Vincenzi B, Fiorentini G, Magnani M, Graziano F. Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: a background for an alternative target therapy. BMC Cancer 2014; 14:357. [PMID: 24886605 PMCID: PMC4046495 DOI: 10.1186/1471-2407-14-357] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 05/12/2014] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. METHODS One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). RESULTS In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. CONCLUSIONS In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.
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Affiliation(s)
- Annamaria Ruzzo
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.
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rs744166 polymorphism of the STAT3 gene is associated with risk of gastric cancer in a Chinese population. BIOMED RESEARCH INTERNATIONAL 2014; 2014:527918. [PMID: 24864251 PMCID: PMC4017712 DOI: 10.1155/2014/527918] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 04/01/2014] [Indexed: 12/11/2022]
Abstract
The aim of this study was to explore the association between polymorphisms in signal transducer and activator of transcription protein 3 (STAT3) and the risk of gastric cancer. In the present study, a case-control study was conducted in which rs2293152 and rs744166 polymorphisms in STAT3 were analyzed in 209 Chinese patients with gastric cancer and 294 cancer-free controls. The genotypes were determined by polymerase chain reaction restriction fragment length polymorphism method. For the rs744166 polymorphism, the TC genotype (adjusted OR = 0.60, 95% CI = 0.39-0.92, and P = 0.020) and CC genotype (adjusted OR = 0.41, 95% CI = 0.21-0.80, and P = 0.009) were associated with a decreased risk of gastric cancer compared to the TT genotype. However, rs2293152 did not show any difference in gastric cancer risk between patients and controls in the CG/CC genotype compared to the GG genotype. Besides, the SNP effects were additive to the effects of environmental factors without any interaction between them in the susceptibility to gastric cancer. Collectively, rs744166 polymorphism might be significantly associated with a decreased risk of gastric cancer in a Chinese population. Additionally, polymorphisms in STAT3, along with environmental factors, might be associated with the development of gastric cancer.
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16
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Lai AZ, Cory S, Zhao H, Gigoux M, Monast A, Guiot MC, Huang S, Tofigh A, Thompson C, Naujokas M, Marcus VA, Bertos N, Sehat B, Perera RM, Bell ES, Page BDG, Gunning PT, Ferri LE, Hallett M, Park M. Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. Sci Signal 2014; 7:ra38. [PMID: 24757178 DOI: 10.1126/scisignal.2004839] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
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Affiliation(s)
- Andrea Z Lai
- 1Department of Biochemistry, McGill University, Montréal, Québec H3A 0G4, Canada
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17
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Yao J, Qian CJ, Ye B, Zhao ZQ, Wei J, Liang Y, Zhang X. Signal transducer and activator of transcription 3 signaling upregulates fascin via nuclear factor-κB in gastric cancer: Implications in cell invasion and migration. Oncol Lett 2014; 7:902-908. [PMID: 24527098 PMCID: PMC3919871 DOI: 10.3892/ol.2014.1804] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 12/20/2013] [Indexed: 12/13/2022] Open
Abstract
Fascin protein plays important roles in tumor metastasis and is prognostically relevant to human gastric cancer (GC). However, its role in the development and progression of GC has not been comprehensively investigated. In the present study, results revealed that upregulation of fascin by interleukin-6 promotes GC cell migration and invasion in a signal transducer and activator of transcription 3 (STAT3)-dependent manner in MKN45 cells. Furthermore, STAT3 directly regulated fascin expression and nuclear factor-κB (NF-κB) bound to the fascin promoter in a STAT3-dependent and Notch-independent manner. Therefore, results demonstrate that STAT3 and NF-κB are required for upregulation of fascin and for cell migration and invasion in MKN45 cells. Effects of the treatments on cell signaling were detected by qPCR, western blot analysis and chromatin immunoprecipitation (ChIP) assay. Cell migration and invasion were analyzed using in vitro scratch wound healing assay, transwell and Matrigel assays, and xenograft model. In addition, the STAT3-NF-κB-fascin signaling axis is identified as a therapeutic target for blocking GC cell invasion and migration.
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Affiliation(s)
- Jun Yao
- Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
| | - Cui-Juan Qian
- Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China ; Insitute of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Bei Ye
- Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Zhi-Qiang Zhao
- Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
| | - Jie Wei
- Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
| | - Yong Liang
- Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
| | - Xin Zhang
- Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China
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18
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Lu SM, Chen MR, Xuan JY, Liu LN, Lv S, Li Y. Relationship between STAT3 activation and epithelial-mesenchymal transition in gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2013; 21:2748-2753. [DOI: 10.11569/wcjd.v21.i26.2748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) in gastric carcinoma (GC) and to analyze their relationship with epithelial-mesenchymal transition (EMT), tumor invasion and metastasis.
METHODS: The expression of STAT3, p-STAT3, E-cadherin and Vimentin proteins in 53 GC specimens and matched normal gastric mucosal specimens was detected by immunohistochemistry. The correlation of expression of STAT3, p-STAT3, E-cadherin and Vimentin proteins with clinicopathological parameters of GC was analyzed.
RESULTS: The positive rates of STAT3, p-STAT3 and Vimentin expression were significantly higher and that of E-cadherin was significantly lower in GC than that in normal gastric mucosal tissues (all P < 0.01). The expression of STAT3, p-STAT3, E-cadherin and Vimentin proteins was significantly correlated with tumor differentiation, depth of invasion, lymph node metastasis and clinical stage (all P < 0.05), but not with gender, age, tumor size (all P > 0.05). STAT3 and p-STAT3 expression was negatively correlated with E-cadherin expression (r = -0.360, -0.335; P = 0.008, 0.014), but positively with Vimentin expression (r = 0.443, 0.346; P = 0.001, 0.011) in GC.
CONCLUSION: STAT3 and p-STAT3 protein expression is up-regulated in GC, and up-regulation of STAT3 and p-STAT3 protein expression in GC is significantly correlated with E-cadherin and Vimentin expression. These findings suggest that EMT may be mediated by the activation of the STAT3 signaling pathway.
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19
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Pohjanen VM, Koivurova OP, Mäkinen JM, Karhukorpi JM, Joensuu T, Koistinen PO, Valtonen JM, Niemelä SE, Karttunen RA, Karttunen TJ. Interleukin 6 gene polymorphism -174 is associated with the diffuse type gastric carcinoma. Genes Chromosomes Cancer 2013; 52:976-82. [PMID: 23893709 DOI: 10.1002/gcc.22093] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 06/28/2013] [Indexed: 12/19/2022] Open
Abstract
The aim of this study was to assess the significance of the interleukin 6 gene polymorphism -174 in gastric cancer risk. The interleukin 6 -174 G/C (rs1800795) gene polymorphisms was analyzed in gastric cancer, peptic ulcer, and nonulcer dyspepsia patients and in healthy control subjects and the data were correlated with the histopathological features of the patients' biopsies. The interleukin 6 -174 GG and GC genotypes have been previously associated with high interleukin 6 serum levels. We discovered that the interleukin 6 -174 GG and GC genotypes are associated with an increased risk of the diffuse histologic subtype of gastric carcinomas (OR: 6.809, P = 0.034), but absent in the intestinal type carcinomas (OR: 1.109, P = 0.908). No significant associations with peptic ulcer, gastric atrophy, or intestinal metaplasia were seen. Our results demonstrate that the interleukin 6 -174 GG and GC genotypes increase the risk of the diffuse type gastric carcinoma, but not the intestinal type gastric carcinoma or its precursor conditions, including atrophy or intestinal metaplasia. Thus, interleukin 6 seems to be an important carcinogenetic factor in the diffuse type gastric adenocarcinoma and its carcinogenetic effect could be noninflammatory.
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Affiliation(s)
- Vesa-Matti Pohjanen
- Department of Pathology, Institute of Diagnostics, University of Oulu and Oulu University Hospital, Oulu, FI-90014, Finland
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20
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Salian-Mehta S, Xu M, Wierman ME. AXL and MET crosstalk to promote gonadotropin releasing hormone (GnRH) neuronal cell migration and survival. Mol Cell Endocrinol 2013; 374:92-100. [PMID: 23648337 PMCID: PMC3690482 DOI: 10.1016/j.mce.2013.04.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 04/24/2013] [Accepted: 04/24/2013] [Indexed: 10/26/2022]
Abstract
The membrane tyrosine kinase receptors, AXL and MET, are implicated in GnRH neuron migration and/or survival. We hypothesized that the receptors with their ligands, GAS6 and HGF, respectively may cross-talk in GnRH neuronal function. In NLT GnRH neuronal cells, MET co-immunoprecipitated with AXL, although HGF or GAS6 did not transphosphorylate AXL or MET, respectively. Co-expression of a kinase dead AXL blocked HGF activation of MET and indirectly AKT and p38MAPK. Silencing of AXL decreased HGF's ability to phosphorylate MET and activate AXL's downstream effectors, p38MAPK and AKT. HGF/MET signaling modulated neuron migration dependent and independent of AXL co-expression and p38MAPK. Conversely, AXL's control of GnRH neuronal survival was dependent on HGF/MET signaling. Together, these data support that the importance of membrane tyrosine kinase receptor crosstalk to regulate neuronal cell-specific developmental functions.
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Affiliation(s)
- Smita Salian-Mehta
- Department of Medicine, University of Colorado, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045
| | - Mei Xu
- Department of Medicine, University of Colorado, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045
| | - Margaret E. Wierman
- Department of Medicine, University of Colorado, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045
- Department of Physiology and Biophysics, University of Colorado, Anschutz Medical Campus, School of Medicine, Aurora, CO 80045
- Research Service VAMC, Denver, CO 80220
- To whom correspondence should be addressed: Margaret E. Wierman, Endocrinology MS8106, University of Colorado Denver,12801 East 17th Ave, RC1 South, Aurora, CO 80045, USA, Tel: 303-724-3952; Fax: 303-724-3920;
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21
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Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K, Hayakawa Y, Takahashi R, Nakata W, Sakitani K, Serizawa T, Hikiba Y, Akanuma M, Shibata W, Maeda S, Koike K. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS One 2013; 8:e60914. [PMID: 23593346 PMCID: PMC3625204 DOI: 10.1371/journal.pone.0060914] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 03/05/2013] [Indexed: 01/29/2023] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial–stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6–positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6−/−) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6−/− mice, compared with WT mice. Impaired tumor development in IL-6−/− mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3–related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell–conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
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Affiliation(s)
- Hiroto Kinoshita
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kei Sakamoto
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Takahashi
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Wachiko Nakata
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kosuke Sakitani
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takako Serizawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yohko Hikiba
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Masao Akanuma
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Wataru Shibata
- Department of Gastroenterology, Yokohama City University, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University, Yokohama, Japan
- * E-mail:
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
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22
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Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, Wu Y, Jiang H, Sun X. STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal 2013; 25:931-938. [PMID: 23333463 DOI: 10.1016/j.cellsig.2013.01.011] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 01/10/2013] [Indexed: 12/20/2022]
Abstract
The interleukin-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway mediates cell proliferation and migration. S-phase kinase-associated protein-2 (Skp2) catalyzes the ubiquitylation of p27 and p21. Here we investigated that the cross-talk of the two pathways regulates motility and invasion of gastric cancer SGC7901 and MGC803 cells. Both cell lines endogenously secret IL-6, and blockage of IL-6 or JAK2 inhibited the activation of JAK2 and STAT3. Depletion of STAT3 downregulated Skp2 expression, and thereby increased the expression of p27 and p21. The depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired the cellular cytoskeleton mainly microtubules; while the depletion of p27 partially restored the impaired ability to migrate, and reversed the impaired microfilaments, further inhibited the ability to invade, but had little effect on microtubules and cellular adhering ability of STAT3-depleted cells. STAT3 depletion inhibited the activity of RhoA and the interaction with stathmin, downregulated the expression of pFAK (phosphorylated focal adhesion kinase), acetylated-tubulin, RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and Sp1, upregulated E-cadherin, and reduced the activities of MMP (matrix metalloproteinase)-2 and -9. The depletion of p27 increased RhoA (Ras homolog family member A) activity, upregulated RECK, and downregulated E-cadherin and Sp1 in STAT3-depleted cells. The results indicate that the interaction between STAT3 and Skp2/p27/p21 pathway plays an important role in mediating the motility, migration and invasion of gastric cancer cells, and inhibition of STAT3 may be a useful therapeutic approach for metastasis of gastric cancer, but caution needs to be taken for its effects on Skp2/p27/p21 pathway.
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Affiliation(s)
- Zheng Wei
- Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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Wang Z, Zhu S, Shen M, Liu J, Wang M, Li C, Wang Y, Deng A, Mei Q. STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1. Carcinogenesis 2013; 34:678-688. [DOI: 10.1093/carcin/bgs361] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Yoon J, Cho SJ, Ko YS, Park J, Shin DH, Hwang IC, Han SY, Nam SY, Kim MA, Chang MS, Lee HS, Kim WH, Lee BL. A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion. BMC Gastroenterol 2013; 13:29. [PMID: 23402362 PMCID: PMC3583822 DOI: 10.1186/1471-230x-13-29] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 01/30/2013] [Indexed: 11/13/2022] Open
Abstract
Background The transcription factor nuclear factor-κB (NF-κB) has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3) in controlling metastatic potential of gastric cancer cells. Methods Immunohistochemistry for NF-κB p65 (RelA), phospho-Tyr705-STAT3 (pSTAT3), or matrix metalloproteinase 9 (MMP9) was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively. Results NF-κB and STAT3 were constitutively activated and were positively correlated (P = 0.038) in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P = 0.001 and P = 0.022, respectively), decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells. Conclusion NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
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Affiliation(s)
- Jiyeon Yoon
- Department of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea
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Kaufmann R, Hascher A, Mussbach F, Henklein P, Katenkamp K, Westermann M, Settmacher U. Proteinase-activated receptor 2 (PAR(2)) in cholangiocarcinoma (CCA) cells: effects on signaling and cellular level. Histochem Cell Biol 2012; 138:913-24. [PMID: 22892662 DOI: 10.1007/s00418-012-1006-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2012] [Indexed: 01/26/2023]
Abstract
In this study, we demonstrate functional expression of the proteinase-activated receptor 2 (PAR(2)), a member of a G-protein receptor subfamily in primary cholangiocarcinoma (PCCA) cell cultures. Treatment of PCCA cells with the serine proteinase trypsin and the PAR(2)-selective activating peptide, furoyl-LIGRLO-NH(2), increased migration across a collagen membrane barrier. This effect was inhibited by a PAR(2)-selective pepducin antagonist peptide (P2pal-18S) and it was also blocked with the Met receptor tyrosine kinase (Met) inhibitors SU 11274 and PHA 665752, the MAPKinase inhibitors PD 98059 and SL 327, and the Stat3 inhibitor Stattic. The involvement of Met, p42/p44 MAPKinases and Stat3 in PAR(2)-mediated PCCA cell signaling was further supported by the findings that trypsin and the PAR(2)-selective agonist peptide, 2-furoyl-LIGRLO-NH(2), stimulated activating phosphorylation of these signaling molecules in cholangiocarcinoma cells. With our results, we provide a novel signal transduction module in cholangiocarcinoma cell migration involving PAR(2)-driven activation of Met, p42/p44 MAPKinases and Stat3.
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Affiliation(s)
- Roland Kaufmann
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Medical Faculty at the Friedrich Schiller University Jena, University Hospital Jena, Drackendorfer Str. 1, 07747 Jena, Germany.
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Okamoto W, Okamoto I, Arao T, Kuwata K, Hatashita E, Yamaguchi H, Sakai K, Yanagihara K, Nishio K, Nakagawa K. Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther 2012; 11:1557-64. [PMID: 22729845 DOI: 10.1158/1535-7163.mct-11-0934] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification.
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Affiliation(s)
- Wataru Okamoto
- Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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Demaria M, Misale S, Giorgi C, Miano V, Camporeale A, Campisi J, Pinton P, Poli V. STAT3 can serve as a hit in the process of malignant transformation of primary cells. Cell Death Differ 2012; 19:1390-7. [PMID: 22402588 DOI: 10.1038/cdd.2012.20] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.
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Affiliation(s)
- M Demaria
- Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Italy
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