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Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo

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Tumor Biology

Abstract

Our previous study demonstrated that Tiam1 was highly expressed in esophageal squamous cell carcinoma (ESCC) tissues. In the present study, we investigated the therapeutic role of Tiam1 siRNA in combination with sorafenib in xenografted human ESCC. Our results demonstrated that expression of Tiam1 protein in EC9706 cells was significantly higher than those in ESCC cells (Eca109 and EC1) and normal esophageal epithelial cells Het-1A (P < 0.05). Tiam1 siRNA markedly suppressed Tiam1 protein expression in tumor tissues of nude mice, but sorafenib did not alter Tiam1 level. In addition, Tiam1 siRNA or sorafenib alone evidently inhibited tumor growth, reduced Ki-67 proliferation index, and induced cell apoptosis in xenografted nude mice, and their combinations had the strongest effect. Notably, Tiam1 siRNA or sorafenib alone obviously increased p27 level, but reduced Mcl-1 and bcl-2 levels in xenografted nude mice, and their combinations reached the best effect. These findings suggest that combination of Tiam1 siRNA with sorafenib may be the novel molecular therapy target for the patients with ESCC.

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References

  1. Lam AK. Molecular biology of esophageal squamous cell carcinoma. Crit Rev Oncol Hematol. 2000;33(2):71–90.

    Article  CAS  PubMed  Google Scholar 

  2. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37(8):S4–S66.

    Article  PubMed  Google Scholar 

  3. Ekman S, Dreilich M, Lennartsson J, Wallner B, Brattstrom D, Sundbom M, et al. Esophageal cancer: current and emerging therapy modalities. Expert Rev Anticancer Ther. 2008;8(9):1433–48.

    Article  PubMed  Google Scholar 

  4. Ke L. Mortality and incidence trends from esophagus cancer in selected geographic areas of China circa 1970–90. Int J Cancer. 2002;102(3):271–4.

    Article  CAS  PubMed  Google Scholar 

  5. Yang CS. Research on esophageal cancer in China: a review. Cancer Res. 1980;40(8 Pt 1):2633–44.

    CAS  PubMed  Google Scholar 

  6. Edwards BK, Brown ML, Wingo PA, Howe HL, Ward E, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst. 2005;97(19):1407–27.

    Article  PubMed  Google Scholar 

  7. Enzinger PC, Ilson DH, Kelsen DP. Chemotherapy in esophageal cancer. Semin Oncol. 1999;26(5 Suppl 15):12–20.

    CAS  PubMed  Google Scholar 

  8. Fleming IN, Gray A, Downes CP. Regulation of the Rac1-specific exchange factor Tiam1 involves both phosphoinositide 3-kinase-dependent and -independent components. Biochem J. 2000;351(Pt 1):173–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Habets GG, Scholtes EH, Zuydgeest D, van der Kammen RA, Stam JC, Berns A, et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell. 1994;77(4):537–49.

    Article  CAS  PubMed  Google Scholar 

  10. Mertens AE, Roovers RC, Collard JG. Regulation of Tiam1-Rac signalling. FEBS Lett. 2003;546(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  11. Wang S, Li S, Yang X, Yang S, Liu S, Liu B, et al. Elevated expression of T-lymphoma invasion and metastasis inducing factor 1 in squamous-cell carcinoma of the head and neck and its clinical significance. Eur J Cancer. 2014;50(2):379–87.

    Article  CAS  PubMed  Google Scholar 

  12. Yu LN, Zhang QL, Li X, Hua X, Cui YM, Zhang NJ, et al. Tiam1 transgenic mice display increased tumor invasive and metastatic potential of colorectal cancer after 1,2-dimethylhydrazine treatment. PLoS One. 2013;8(9):e73077.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Zhu JM, Yu PW. Downregulation of T cell lymphoma invasion and metastasisinducing factor 1 induces cytoskeletal rearrangement and inhibits the invasive capacity of gastric cancer cells. Mol Med Rep. 2013;8(2):425–33.

    PubMed  Google Scholar 

  14. Zhu JM, Yu PW. Effects of Tiam 1 on invasive capacity of gastric cancer cells in vitro and underlying mechanisms. Asian Pac J Cancer Prev. 2013;14(1):201–8.

    Article  PubMed  Google Scholar 

  15. Shi YL, Miao RZ, Cheng L, Guo XB, Yang B, Jing CQ, et al. Up-regulation of T-lymphoma and metastasis gene 1 in gastric cancer and its involvement in cell invasion and migration. Chin Med J (Engl). 2013;126(4):640–5.

    CAS  Google Scholar 

  16. Wu YQ, Xie YY. Peng G: [Effects of Tiam1 on invasion and metastasis of breast carcinoma and its mechanisms]. Zhonghua Zhong Liu Za Zhi. 2012;34(11):831–4.

    CAS  PubMed  Google Scholar 

  17. Buchsbaum RJ, Connolly BA, Feig LA. Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade. Mol Cell Biol. 2002;22(12):4073–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59(5):561–74.

    Article  CAS  PubMed  Google Scholar 

  19. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.

    Article  CAS  PubMed  Google Scholar 

  20. Yu C, Friday BB, Lai JP, Yang L, Sarkaria J, Kay NE, et al. Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther. 2006;5(9):2378–87.

    Article  CAS  PubMed  Google Scholar 

  21. Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. 2007;12(4):426–37.

    Article  CAS  PubMed  Google Scholar 

  22. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(26):4293–300.

    Article  CAS  PubMed  Google Scholar 

  23. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, et al. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007;12(2):191–200.

    Article  CAS  PubMed  Google Scholar 

  24. Ji Z, Yang G, Shahzidi S, Tkacz-Stachowska K, Suo Z, Nesland JM, et al. Induction of hypoxia-inducible factor-1alpha overexpression by cobalt chloride enhances cellular resistance to photodynamic therapy. Cancer Lett. 2006;244(2):182–9.

    Article  CAS  PubMed  Google Scholar 

  25. Hou G, Zhang Q, Wang L, Liu M, Wang J, Xue L. mTOR inhibitor rapamycin alone or combined with cisplatin inhibits growth of esophageal squamous cell carcinoma in nude mice. Cancer Lett. 2010;290(2):248–54.

    Article  CAS  PubMed  Google Scholar 

  26. Kang MR, Kang JS, Yang JW, Kim BG, Kim JA, Jo YN, et al. Gene expression profiling of KBH-A42, a novel histone deacetylase inhibitor, in human leukemia and bladder cancer cell lines. Oncol Lett. 2012;3(1):113–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Huynh H, Soo KC, Chow PK, Panasci L, Tran E. Xenografts of human hepatocellular carcinoma: a useful model for testing drugs. Clin Cancer Res. 2006;12(14 Pt 1):4306–14.

    Article  CAS  PubMed  Google Scholar 

  28. Chen G, Gong M, Yan M, Zhang X. Sevoflurane induces endoplasmic reticulum stress mediated apoptosis in hippocampal neurons of aging rats. PLoS One. 2013;8(2):e57870.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Lu Z, Liu H, Xue L, Xu P, Gong T, Hou G. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706. Int J Oncol. 2008;32(3):643–51.

    CAS  PubMed  Google Scholar 

  30. Liu H, Shi G, Liu X, Wu H, Fan Q, Wang X. Overexpression of Tiam1 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncol Rep. 2011;25(3):841–8.

    CAS  PubMed  Google Scholar 

  31. Liu Y, Ding Y, Huang J, Wang S, Ni W, Guan J, et al. MiR-141 Suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS One. 2014;9(2):e88393.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Huang J, Ye X, Guan J, Chen B, Li Q, Zheng X, et al. Tiam1 is associated with hepatocellular carcinoma metastasis. Int J Cancer. 2013;132(1):90–100.

    Article  CAS  PubMed  Google Scholar 

  33. Liu L, Zhang Q, Zhang Y, Wang S, Ding Y. Lentivirus-mediated silencing of Tiam1 gene influences multiple functions of a human colorectal cancer cell line. Neoplasia. 2006;8(11):917–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Carlo-Stella C, Locatelli SL, Giacomini A, Cleris L, Saba E, Righi M, et al. Sorafenib inhibits lymphoma xenografts by targeting MAPK/ERK and AKT pathways in tumor and vascular cells. PLoS One. 2013;8(4):e61603.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Kusano H, Ogasawara S, Akiba J, Nakayama M, Ueda K, Yano H. Antiproliferative effects of sorafenib and pegylated IFNalpha2b on human liver cancer cells in vitro and in vivo. Int J Oncol. 2013;42(6):1897–903.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Pawaskar DK, Straubinger RM, Fetterly GJ, Hylander BH, Repasky EA, Ma WW, et al. Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. Cancer Chemother Pharmacol. 2013;71(5):1231–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Subramanian N, Navaneethakrishnan S, Biswas J, Kanwar RK, Kanwar JR, Krishnakumar S. RNAi mediated Tiam1 gene knockdown inhibits invasion of retinoblastoma. PLoS One. 2013;8(8):e70422.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rygiel TP, Mertens AE, Strumane K, van der Kammen R, Collard JG. The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation. J Cell Sci. 2008;121(Pt 8):1183–92.

    Article  CAS  PubMed  Google Scholar 

  39. Minard ME, Ellis LM, Gallick GE. Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells. Clin Exp Metastasis. 2006;23(5–6):301–13.

    Article  CAS  PubMed  Google Scholar 

  40. Galmiche A, Chauffert B, Barbare JC. New biological perspectives for the improvement of the efficacy of sorafenib in hepatocellular carcinoma. Cancer Lett. 2014;346(2):159–62.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang YN, Wu XY, Zhong N, Deng J, Zhang L, Chen W, et al. Stimulatory effects of sorafenib on human nonsmall cell lung cancer cells in vitro by regulating MAPK/ERK activation. Mol Med Rep. 2014;9(1):365–9.

    CAS  PubMed  Google Scholar 

  42. Huang CY, Lin CS, Tai WT, Hsieh CY, Shiau CW, Cheng AL, et al. Sorafenib enhances radiation-induced apoptosis in hepatocellular carcinoma by inhibiting STAT3. Int J Radiat Oncol Biol Phys. 2013;86(3):456–62.

    Article  CAS  PubMed  Google Scholar 

  43. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999;50:401–23.

    Article  CAS  PubMed  Google Scholar 

  44. Lloyd RV, Jin L, Qian X, Kulig E. Aberrant p27kip1 expression in endocrine and other tumors. Am J Pathol. 1997;150(2):401–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Bose P, Grant S. Mcl-1 as a therapeutic target in acute myelogenous leukemia (AML). Leuk Res Rep. 2013;2(1):12–4.

    PubMed Central  PubMed  Google Scholar 

  46. Lam M, Dubyak G, Chen L, Nunez G, Miesfeld RL, Distelhorst CW. Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci U S A. 1994;91(14):6569–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993;75(2):241–51.

    Article  CAS  PubMed  Google Scholar 

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Liu, H., Wang, X., Shi, G. et al. Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo. Tumor Biol. 35, 8249–8258 (2014). https://doi.org/10.1007/s13277-014-2083-x

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  • DOI: https://doi.org/10.1007/s13277-014-2083-x

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