title: Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin.
abstract: 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.
authors.affiliation: State Key Laboratory of Cancer Biology & Digestive Diseases, of Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Yin
authors.forename: Yulei
authors.initials: Y
authors.lastname: Du
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.forename: Shuhui
authors.initials: S
authors.lastname: Liang
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenqi
authors.initials: W
authors.lastname: Du
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D004317:Doxorubicin; D019908:Proto-Oncogene Proteins c-raf; D002945:Cisplatin