Expression of the mitotic-arrest deficiency 2 is associated with chemotherapy resistance in ovarian serous adenocarcinoma

Nakano,Yusuke; Sumi,Toshiyuki; Teramae,Masatomo; Morishita,Masanari; Fukuda,Takeshi; Terada,Hiroyuki; Yoshida,Hiroyuki; Matsumoto,Yoshinari; Yasui,Tomoyo; Ishiko,Osamu

doi:10.3892/or.2012.1907

Expression of the mitotic-arrest deficiency 2 is associated with chemotherapy resistance in ovarian serous adenocarcinoma

Authors:
- Yusuke Nakano
- Toshiyuki Sumi
- Masatomo Teramae
- Masanari Morishita
- Takeshi Fukuda
- Hiroyuki Terada
- Hiroyuki Yoshida
- Yoshinari Matsumoto
- Tomoyo Yasui
- Osamu Ishiko
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
Published online on: July 12, 2012 https://doi.org/10.3892/or.2012.1907
Pages: 1200-1204

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mitotic-arrest deficiency 2 (MAD2) is a key component of spindle assembly checkpoint (SAC) function; SAC mediates spindle microtubule attachment to kinetochores on chromosomes and chromosomal segregation during mitosis. To determine whether MAD2 expression is associated with chemotherapy resistance in ovarian serous adenocarcinoma, we reviewed tumor samples from 41 cases of ovarian serous adenocarcinoma at Osaka City University Medical School Hospital (Osaka, Japan), 2000-2007. Of the 41 cases, 24 were recurrent and 17 were not recurrent. Expression of MAD2 was investigated in paraffin-embedded sections using a MAD2 antibody. Quantitative analysis of MAD2 expression gave mean weighted scores of 4.3 for the relapsed group and 7.2 for the relapse-free group; the expression was, thus, significantly greater in the relapse-free group compared to the relapsed group (P=0.023). When the 41 cases were classified into low- and high-expression, these classifications showed no significant difference in terms of progression-free survival (P=0.0685), however, overall survival for the low-expression group was significantly shorter than that of the high-expression group (P=0.0188). The present study implies that MAD2 expression levels can indicate sensitivity to anticancer agents, and risk for recurrence.

View References

1	Heintz AP, Odicino F, Maisonneuve P, et al: Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynecol Obstet. 95:S161–S192. 2006.PubMed/NCBI
2	Hardwick KG: Checkpoint signaling: Mad2 conformers and signal propagation. Curr Biol. 15:R122–R124. 2005. View Article : Google Scholar : PubMed/NCBI
3	Lopez-Girona A, Furnari B, Mondesert O and Russell P: Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein. Nature. 397:172–175. 1999. View Article : Google Scholar : PubMed/NCBI
4	Wang X, Jin DY, Ng RW, Feng H, Wong YC, Cheung AL and Tsao SW: Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res. 62:1662–1668. 2002.PubMed/NCBI
5	Li R and Murray A: Feedback control of mitosis in budding yeast. Cell. 66:519–531. 1991. View Article : Google Scholar : PubMed/NCBI
6	Orr-Weaver TL and Weinberg RA: A checkpoint on the road to cancer. Nature. 392:223–224. 1998. View Article : Google Scholar : PubMed/NCBI
7	Yoon DS, Wersto RP, Zhou W, Chrest FJ, Garret ES, Kwon TK and Gabrielson E: Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am J Pathol. 161:391–397. 2002. View Article : Google Scholar : PubMed/NCBI
8	Lengauer C, Kinzler KW and Vogelstein B: Genetic instability in colorectal cancer. Nature. 386:623–627. 1997. View Article : Google Scholar : PubMed/NCBI
9	Lengauer C, Kinzler KW and Vogelstein B: Genetic instability in human cancer. Nature. 396:643–649. 1998. View Article : Google Scholar
10	Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW and Benezra R: Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell. 11:9–23. 2007. View Article : Google Scholar : PubMed/NCBI
11	Li GQ, Li H and Zhang HF: Mad2 and p53 expression profiles in colorectal cancer and its clinical significance. World J Gastroenterol. 9:1972–1975. 2003.PubMed/NCBI
12	Wang L, Yin F, Du Y, Du W, Chen B, Zhang Y, Wu K, Ding J, Liu J and Fan D: MAD2 as a key component of mitotic checkpoint: A probable prognostic factor for gastric cancer. Am J Clin Pathol. 131:793–801. 2009. View Article : Google Scholar : PubMed/NCBI
13	Chen X, Cheung ST, So S, et al: Gene expression patterns in human liver cancers. Mol Biol Cell. 13:1929–1939. 2002. View Article : Google Scholar PubMed/NCBI
14	Yu L, Guo WC, Zhao SH, Tang J and Chen JL: Mitotic arrest defective protein 2 expression abnormality and its clinicopathologic significance in human osteosarcoma. APMIS. 118:222–229. 2010. View Article : Google Scholar : PubMed/NCBI
15	Zhang SH, Xu AM, Chen XF, Li DH, Sun MP and Wang YJ: Clinicopathologic significance of mitotic arrest defective protein2 overexpression in hepatocellular carcinoma. Hum Pathol. 39:1827–1834. 2008. View Article : Google Scholar : PubMed/NCBI
16	Nakano Y, Sumi T, Morishita M, Fukuda T, Nobeyama H, Yoshida H, Matsumoto Y, Yasui T and Ishiko O: Mitotic arrest deficiency 2 induces carcinogenesis in mucinous ovarian tumors. Oncol Lett. 3:281–286. 2012.PubMed/NCBI
17	Wang X, Jin DY, Wong YC, Cheung AL, Chun AC, Lo AK, Liu Y and Tsao SW: Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells. Carcinogenesis. 21:2293–2297. 2000. View Article : Google Scholar : PubMed/NCBI
18	Fung MK, Cheung HW, Ling MT, Cheung AL, Wong YC and Wang X: Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumor cells. Br J Cancer. 95:475–484. 2006. View Article : Google Scholar : PubMed/NCBI
19	Cheung HW, Chun AC, Wang Q, Deng W, Hu L, Guan XY, Nicholls JM, Ling MT, Chuan Wong Y, Tsao SW, et al: Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer Res. 66:4357–4367. 2006. View Article : Google Scholar : PubMed/NCBI
20	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: Bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
21	Wu CW, Chi CW and Huang TS: Elevated level of spindle checkpoint MAD2 correlates with cellular mitotic arrest, but not with aneuploidy and clinicopathological characteristics in gastric cancer. World J Gastroenterol. 10:3240–3244. 2004.PubMed/NCBI
22	Schvartzman JM, Duijf PH, Sotillo R, Coker C and Benezra R: Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell. 19:701–714. 2011. View Article : Google Scholar : PubMed/NCBI
23	Sotillo R, Schvartzman JM, Socci ND and Beneztra R: Mad2-induced chromosome instability leads to lung tumor relapse after oncogene withdrawal. Nature. 464:436–440. 2010. View Article : Google Scholar : PubMed/NCBI
24	Zhou J, Yao J and Joshi HC: Attachment and tension in the spindle assembly checkpoint. J Cell Sci. 115:3547–3555. 2002. View Article : Google Scholar : PubMed/NCBI
25	Buke DJ and Stukenberg PT: Linking kinetochoremicrotubule binding to the spindle checkpoint. Dev Cell. 14:474–479. 2008. View Article : Google Scholar : PubMed/NCBI
26	McGrogan BT, Gilmartin B, Carney DN and McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 1785:96–132. 2008.PubMed/NCBI
27	Prencipe M, Fitzpatrick P, Gorman S, Tosetto M, Klinger R, Furlong F, Harrison M, O'Connor D, Roninson IB, O'Sullivan J and McCann A: Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro. Br J Cancer. 101:1900–1908. 2009. View Article : Google Scholar : PubMed/NCBI
28	Hao X, Zhou Z, Ye S, Zhou T, Lu Y, Ma D and Wang S: Effect of Mad2 on paclitaxel-induced cell death in ovarian cancer cells. J Huazhong Univ Sci Technolog Med Sci. 30:620–625. 2010. View Article : Google Scholar : PubMed/NCBI
29	Du Y, Yin F, Liu C, Hu S, Qang J, Xie H, Hong L and Fan D: Depression of Mad2 inhibits apoptosis of gastric cancer cells by upregulating Bcl-2 and interfering mitochondrion pathway. Biochem Biophys Res Commun. 345:1092–1098. 2006. View Article : Google Scholar : PubMed/NCBI
30	Morishita M, Sumi T, Nakano Y, Fukuda T, Nobeyama H, Yoshida H, Matsumoto Y, Yasui T and Ishiko O: Expression of mitotic-arrest deficiency 2 predicts the efficacy of neoadjuvant chemotherapy for locally advanced uterine cervical cancer. Exp Ther Med. 3:341–346. 2012.PubMed/NCBI