Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin
- 412 Downloads
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.
KeywordsGastric cancer Mitotic arrest-deficient 2 Mitotic spindle checkpoint Survivin Drug resistance siRNA Apoptosis
mitotic arrest-deficient 2
multi-drug resistance-associated protein
small interfering RNA
We are grateful to Dr. Bin Guo for his proofreading of the manuscript. We thank technician Yunxin Cao for excellent technical assistance. This study was supported in part by grants from the Chinese National Foundation of National Sciences (C03031905, 30973422, 30600551, and 30530780).
- 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):837–40.Google Scholar
- 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. 185211–8.Google Scholar
- 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;26:201–4.Google Scholar
- 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;2:672–6.Google Scholar
- 31.Musacchio, Hardwick KG (2002) The spindle checkpoint: structural insights into dynamic signaling. Nat. Rev. Mol. Cell. Biol. 3731–41.Google Scholar
- 32.Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores from epigenetics to mitotic checkpoint signaling. Cell 112407–21.Google Scholar