Enhanced expression of suppresser of cytokine signaling 3 inhibits the IL-6-induced epithelial-to-mesenchymal transition and cholangiocarcinoma cell metastasis

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• 作者：Qing-Xin Zhou (1)
  Xing-Ming Jiang (1)
  Zhi-Dong Wang (1)
  Chun-Long Li (1)
  Yun-Fu Cui (1)
  
  1. Department of Hepato-Biliary-Pancreatic Surgery ; The Second Affiliated Hospital ; Harbin Medical University ; No. 246 Xuefu Road ; Harbin ; 150086 ; Heilongjiang Province ; China
  
• 关键词：EMT ; IL ; 6 ; SOCS3 ; Cholangiocarcinoma
• 刊名：Medical Oncology
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：32
• 期：4
• 全文大小：2,876 KB
• 参考文献：1. Rizvi, S, Gores, GJ (2013) Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145: pp. 1215-1229 CrossRef
  2. DeOliveira, ML, Cunningham, SC, Cameron, JL, Kamangar, F, Winter, JM, Lillemoe, KD (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245: pp. 755-762 CrossRef
  3. Lau, SH, Lau, WY (2012) Current therapy of hilar cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 11: pp. 12-17 CrossRef
  4. Kalluri, R, Weinberg, RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119: pp. 1420-1428 CrossRef
  5. Gores, GJ (2003) Cholangiocarcinoma: current concepts and insights. Hepatology 37: pp. 961-969 CrossRef
  6. Matsumoto, K, Fujii, H, Michalopoulos, G, Fung, JJ, Demetris, AJ (1994) Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro. Hepatology 20: pp. 376-382 CrossRef
  7. Meng, F, Yamagiwa, Y, Ueno, Y, Patel, T (2006) Over-expression of Interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol 44: pp. 1055-1065 CrossRef
  8. Yokomuro, S, Tsuji, H, Lunz, JG, Sakamoto, T, Ezure, T, Murase, N (2000) Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells. Hepatology 32: pp. 26-35 CrossRef
  9. Nehls, O, Gregor, M, Klump, B (2004) Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 24: pp. 139-154 CrossRef
  10. Bromberg, J, Wang, TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15: pp. 79-80 CrossRef
  11. Isomoto, H, Kobayashi, S, Werneburg, NW, Bronk, SF, GuCCAiardi, ME, Frank, DA (2005) Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 42: pp. 1329-1338 CrossRef
  12. Sullivan, NJ, Sasser, AK, Axel, AE, Vesuna, F, Raman, V, Ramirez, N (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28: pp. 2940-2947 CrossRef
  13. Yadav, A, Kumar, B, Datta, J, Teknos, TN, Kumar, P (2011) IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 9: pp. 1658-1667 CrossRef
  14. Zhao, Z, Cheng, X, Wang, Y, Han, R, Li, L, Xiang, T (2014) Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PLoS ONE 9: pp. e95884 CrossRef
  15. Inagaki-Ohara, K, Kondo, T, Ito, M, Yoshimura, A (2013) SOCS, inflammation, and cancer. JAK-STAT 2: pp. e24053 CrossRef
  16. Croker, BA, Kiu, H, Nicholson, SE (2008) SOCS regulation of the JAK/STAT signaling pathway. Semin Cell Dev Biol 19: pp. 414-422 CrossRef
  17. Weber, A, Hengge, UR, Bardenheuer, W, Tischoff, I, Sommerer, F, Markwarth, A (2005) SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene 24: pp. 6699-6708 CrossRef
  18. He, B, You, L, Uematsu, K, Zang, K, Xu, Z, Lee, AY (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100: pp. 14133-14138 CrossRef
  19. Niwa, Y, Kanda, H, Shikauchi, Y, Saiura, A, Matsubara, K, Kitagawa, T (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24: pp. 6406-6417
  20. Isomoto, H, Mott, JL, Kobayashi, S, Werneburg, NW, Bronk, SF, Haan, S (2007) Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 132: pp. 384-396 CrossRef
  21. Rossa, C, Sommer, G, Spolidorio, LC, Rosenzweig, SA, Watson, DK, Kirkwood, KL (2012) Loss of expression and function of socs3 is an early event in HNSCC: altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. PLoS ONE 7: pp. e45197 CrossRef
  22. Jiang, GX, Zhong, XY, Cui, YF, Liu, W, Tai, S, Wang, ZD (2010) IL-6/STAT3/TFF3 signaling regulates human biliary epithelial cell migration and wound healing in vitro. Mol Biol Rep 37: pp. 3813-3818 CrossRef
  23. Lopez-Novoa, JM, Nieto, MA (2009) Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 1: pp. 303-314 CrossRef
  24. Grivennikov, SI, Karin, M (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 1: pp. i104-i108 CrossRef
  25. Colomiere, M, Ward, AC, Riley, C, Trenerry, MK, Cameron-Smith, D, Findlay, J (2009) Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial鈥搈esenchymal transition in ovarian carcinomas. Br J Cancer 100: pp. 134-144 CrossRef
  26. Yamada, D, Kobayashi, S, Wada, H, Kawamoto, K, Marubashi, S, Eguchi, H (2013) Role of crosstalk between interleukin-6 and transforming growth factor-beta 1 in epithelial鈥搈esenchymal transition and chemoresistance in biliary tract cancer. Eur J Cancer 49: pp. 1725-1740 CrossRef
  27. Sasaki, A, Yasukawa, H, Suzuki, A, Kamizono, S, Syoda, T, Kinjyo, I (1999) Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. Genes Cells 4: pp. 339-351 CrossRef
  28. Evans, MK, Yu, CR, Lohani, A, Mahdi, RM, Liu, X, Trzeciak, AR (2007) Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals. Oncogene 26: pp. 1941-1948 CrossRef
  29. Bellezza, I, Neuwirt, H, Nemes, C, Cavarretta, IT, Puhr, M, Steiner, H (2006) Suppressor of cytokine signaling-3 antagonizes cAMP effects on proliferation and apoptosis and is expressed in human prostate cancer. Am J Pathol 169: pp. 2199-2208 CrossRef
  30. Diakos, CI, Charles, KA, McMillan, DC, Clarke, SJ (2014) Cancer-related inflammation and treatment effectiveness. Lancet Oncol 15: pp. e493-e503 CrossRef
  
• 刊物主题：Oncology; Hematology; Pathology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-131X

文摘

It was recently demonstrated that interleukin-6 (IL-6) induces the epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma (CCA), but the underlying molecular mechanism remains to be explored. In this study, we studied the role of suppresser of cytokine signaling 3 (SOCS3), a negative feedback regulator of IL-6/STAT3, in the IL-6-induced EMT in CCA. Treatment with IL-6 induced the EMT by decreasing the E-cadherin expression and increasing the expression of N-cadherin and vimentin. Using wound healing and invasion assays, we found that IL-6 promoted cell motility. Further, a stably transfected cell line overexpressing SOCS3 was constructed. Enhanced SOCS3 expression decreased IL-6-induced cell invasion and EMT in parallel with downregulating the IL-6/STAT3 pathway. In contrast, SOCS3 silencing using siRNA exhibited no effect on the cell invasive ability and EMT. Finally, an in vivo study indicated that the enhancement of SOCS3 expression decreased metastasis compared with the control, and this effect was achieved by the repression of p-STAT3, N-cadherin and vimentin, and the induction of E-cadherin assessed by Western blot analysis. Our results suggest that enhanced expression of SOCS3 can antagonize IL-6-induced EMT and cell metastasis by abrogating the IL-6/STAT3 pathway. These data establish that SOCS3 plays a role in the EMT in CCA and may provide novel therapeutic strategies for CCA.