Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin

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• 作者：Li Wang (1)
  Fang Yin (1)
  Yulei Du (1)
  Bei Chen (1)
  Shuhui Liang (1)
  Yongguo Zhang (1)
  Wenqi Du (1)
  Kaichun Wu (1)
  Jie Ding (1)
  Daiming Fan (1)
  
• 关键词：Gastric cancer ; Mitotic arrest ; deficient 2 ; Mitotic spindle checkpoint ; Survivin ; Drug resistance ; siRNA ; Apoptosis
• 刊名：Tumor Biology
• 出版年：2010
• 出版时间：June 2010
• 年：2010
• 卷：31
• 期：3
• 页码：225-232
• 全文大小：331KB
• 参考文献：1. Fang G, Yu H, Kirschne MW. Control of mitotic transitions by the anaphase-promoting complex phil. Trans R Soc Lond. 1999;B354:1583鈥?0. CrossRef
  2. Hisaoka M, Matsuyama A, Hashimoto H. Aberrant MAD2 expression in soft-tissue sarcoma. Pathol Int. 2008;58:329鈥?3. CrossRef
  3. Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell. 2000;101(6):635鈥?5. CrossRef
  4. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, et al. MAD2 haploin sufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409:355鈥?. CrossRef
  5. Pennisi E. Cell division gatekeepers identified. Science. 1998;279:477鈥?. CrossRef
  6. Hernando E, Orlow I, Liberal V, Nohales G, Benezra R, Cordon-Cardo C. Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int J Cancer. 2001;95(4):223鈥?. CrossRef
  7. Gemma A, Hosoya Y, Seike M, Uematsu K, Kurimoto F, Hibino S, et al. Genomic structure of the human MAD2 gene and mutation analysis in human lung and breast cancers. Lung Cancer. 2001;32(3):289鈥?5. CrossRef
  8. Imai Y, Shiratori Y, Kato N, Inoue T, Omata MJ. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Cancer Res. 1999;90(8):837鈥?0.
  9. Percy MJ, Myrie KA, Neeley CK, Azim JN, Ethier SP, Petty EM. Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells. Genes, Chromosomes Cancer. 2000;29(4):356鈥?2. CrossRef
  10. Li Y, Benezra R. Identification of a human mitotic checkpoint gene: hsMAD2. Science. 1996;274:246鈥?. CrossRef
  11. Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H, et al. Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes,hsMAD2 and p55CDC, in human lung cancers. Oncogene. 1999;18:4295鈥?00. CrossRef
  12. Wang X, Jin D-Y, Wong YC, Cheung ALM, Chun ACS, Lo AKF. Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells. Carcinogenesis. 2000;21:2293鈥?. CrossRef
  13. Hisaoka M, Matsuyama A, Hashimoto H. Aberrant MAD2 expression in soft-tissue sarcoma. Pathol Int. 2008;58(6):329鈥?3. CrossRef
  14. Ruddy DA, Gorbatcheva B, Yarbrough G, Schlegel R, Monahan JE. No somatic mutations detected in the Mad2 gene in 658 human tumors. Mutat Res. 2008;641(1-2):61鈥?.
  15. Wang X, Jin D-Y, Ng RWM, Feng H, Wong YC, Cheung ALM, et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res. 2002;62:1662鈥?.
  16. Zhao YQ, You H, Liu F, An HZ, Shi YQ, Yu Q et al (2002) Differentially expressed gene profiles between multidrug resistant gastric adenocarcinoma cells and their parental cells. Cancer Lett. 185211鈥?.
  17. Yin F, Hu WH, Qiao TD, Fan DM. Multidrug resistant effect of alternative splicing form of MAD2 gene-MAD2beta on human gastric cancer cell. Chin J Oncol. 2004;26:201鈥?.
  18. Yin F, Du Y, Hu W, Qiao T, Ding J, Wu K, et al. Mad2尾, an alternative variant of Mad2 reduce mitotic arrest and apoptosis of gastric cancer cells induced by adriamycin. Life Sci. 2006;78:1277鈥?6. CrossRef
  19. Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, et al. Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004;315(3):686鈥?1. CrossRef
  20. Smits VA, Klompmarker R, Arnaudm L, Rijksen G, Nigg EA, Medema RH. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol. 2000;2:672鈥?.
  21. Huang T-S, Duyster J, Wang JYJ. Biological response to phorbolester determined by alternative G1 pathway. Proc Natl Acad Sci USA. 1995;92:4793鈥?. CrossRef
  22. Huang T-S, Shu C-H, Yang WK, Whang-Peng J. Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331 induced apoptosis. Cancer Res. 1997;57:2974鈥?.
  23. Huang T-S, Yang WK, Whang-Peng J. GL331-induced disruption of cyclin B1/CDC2 complex and inhibition of CDC2 kinase activity. Apoptosis. 1996;1:213鈥?. CrossRef
  24. Sudo T, Nitta M, Saya H, Ueno NT. Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res. 2004;64(7):2502鈥?. CrossRef
  25. Schwartz GK. Development of cell cycle active drugs for the treatment of gastrointestinal cancers: a new approach to cancer therapy. J Clin Oncol. 2005;20:4499鈥?08. CrossRef
  26. Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59(4):928鈥?2. CrossRef
  27. Garber PM, Rine J. Overlapping roles of the spindle assembly and DNA damage checkpoints in the cell-cycle response to altered chromosomes in Saccharomyces cerevisiae. Genetics. 2002;161:521鈥?4.
  28. Mikhailov A, Cole RW, Rieder CL. DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol. 2002;12:1797鈥?06. CrossRef
  29. Tulub AA, Stefanov VE. Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes. Int J Biol Macromol. 2001;28:191鈥?. CrossRef
  30. Chow JP, Siu WY, Fung TK, Chan WM, Lau A, Arooz T, et al. DNA damage during the spindle-assembly checkpoint degrades CDC25A, inhibits cyclin-CDC2 complexes, and reverses cells to interphase. Mol Biol Cell. 2003;14(10):3989鈥?002. CrossRef
  31. Musacchio, Hardwick KG (2002) The spindle checkpoint: structural insights into dynamic signaling. Nat. Rev. Mol. Cell. Biol. 3731鈥?1.
  32. Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores from epigenetics to mitotic checkpoint signaling. Cell 112407鈥?1.
  33. Glotzer M. Mitosis: don鈥檛 get mad, get even. Curr Biol. 1996;6:1592鈥?. CrossRef
  34. Wang X, Jin D-Y, Wong HL, Feng H, Wong Y-C, Tsao SW. MAD2-induced sensitisation to vincristine is associated with mitotic arrest and Raf/Bcl-2 phosphorylation in nasopharyngeal carcinoma cells. Oncogene. 2003;22:109鈥?6. CrossRef
  35. Fung MKL, Han H-Y, Leung SCL, Cheung HW, Cheung ALM, Wong Y-C, et al. MAD2 interacts with DNA repair proteins and negatively regulates DNA damage repair. J Mol Biol. 2008;381(1):24鈥?4. CrossRef
  36. Zhang P, Cong B, Yuan H, Chen L, Lv Y, Bai C, et al. Overexpression of spindlin1 induces metaphase arrest and chromosomal instability. J Cell Physiol. 2008;217(2):400鈥?. CrossRef
  37. Du Y, Yin F, Liu C, Hu S, Wang J, Xie H, et al. Depression of MAD2 inhibits apoptosis of gastric cancer cells by upregulating Bcl-2 and interfering mitochondrion pathway. Biochem Biophys Res Commun. 2006;345(3):1092鈥?. CrossRef
  38. Fujita T, Washio K, Takabatake D, Takahashi H, Yoshitomi S, Tsukuda K, et al. Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance. Int J Cancer. 2005;117:670鈥?2. CrossRef
  39. Zhao YQ, You H, Liu F, An HZ, Shi YQ, Yu Q, et al. Differentially expressed gene profiles between multidrug resistant gastric adenocarcinoma cells and their parental cells. Cancer Lett. 2002;185:211鈥?. CrossRef
  
• 作者单位：Li Wang (1)
  Fang Yin (1)
  Yulei Du (1)
  Bei Chen (1)
  Shuhui Liang (1)
  Yongguo Zhang (1)
  Wenqi Du (1)
  Kaichun Wu (1)
  Jie Ding (1)
  Daiming Fan (1)
  
  1. State Key Laboratory of Cancer Biology & Digestive Diseases, of Xijing Hospital, Fourth Military Medical University, Xi鈥檃n, 710032, China
  
• ISSN：1423-0380

文摘

Mitotic arrest-deficient 2 (MAD2) is one of the essential mitotic spindle checkpoint regulators, and it can protect cells from aberrant chromosome segregation. The Mad2 gene is very rarely mutated in many kinds of human cancer, but aberrantly reduced expression of MAD2 has been correlated with defective mitotic checkpoints in several human cancers. We have previously found that the MAD2 expression level is also shown to be associated with the multidrug resistance of tumour cells. In this study, we constructed a small interfering RNA (siRNA) eukaryotic expression vector of MAD2 and downregulated MAD2 expression in the gastric cancer cell line SGC7901 by transfection of MAD2-siRNA. SGC7901 cells stably transfected with the MAD2-siRNA exhibited significantly increased expression of phosphorylated survivin protein and enhanced drug resistance. Furthermore, MAD2-siRNA suppressed the proliferation of SGC7901 cells and inhibited tumour formation in athymic nude mice. This study clearly reveals that downregulation of MAD2 could regulate the cell cycle, increase proliferation, and improve the drug resistance of gastric cancer cells by regulating the activation of phosphorylated survivin. It also suggests both that MAD2 might play an important role in the development of human gastric cancer and that silencing the MAD2 gene may help to deal with the multidrug resistance of gastric cancer cells.