ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death

Abstract

ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined the mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in the carcinomas than in the control non-neoplastic ovarian tissue. Among the histological sub-types of serous, endometrioid, mucinous and clear cell carcinomas, the ADAM9m expression was highest in the clear cell carcinomas. Immunohistochemistry demonstrated that all the clear cell carcinoma samples exhibit ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, the viability was significantly reduced and apoptosis increased in ADAM9m knock-down cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data demonstrate, to the best of our knowledge, for the first time that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in the cisplatin-resistance.

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