Ovarian serous carcinomas acquire cisplatin resistance and increased invasion through downregulation of the high-temperature-required protein A2 (HtrA2), following repeated treatment with cisplatin

High-temperature-required protein A2 (HtrA2) is one of the serine proteases related to apoptosis. HtrA2 protein expression has been associated with cisplatin resistance and poor prognosis in ovarian serous adenocarcinoma (SAC). The aim of this study was to understand the influence of HtrA2 on repeated treatment with cisplatin. The change in HtrA2 expression in 31 ovarian cancers was investigated by immunohistochemical analysis, before and after cisplatin-based chemotherapy, and the association between HtrA2 expression after chemotherapy and prognosis was analyzed. The association between the change in HtrA2 and proteins associated with LATS1 in ovarian serous cancer cell lines after repeated treatment with cisplatin was evaluated in vitro. In immunohistochemical analysis, repeated cisplatin treatment induced downregulation of HtrA2 protein expression, before and after cisplatin-based chemotherapy in SAC. Progression-free survival and overall survival of SAC with low expression of HtrA2 were worse than those with high expression. In vitro analysis using cisplatin-sensitive ovarian cancer cell lines, KF28, and cisplatin-resistant cancer cell lines, KFr13, obtained from KF28 by repeated cisplatin treatment, showed that HtrA2 protein expression was lower in KFr13 than in KF28. Furthermore, KFr13 had a higher invasive capacity than KF28. Next, downregulation of HtrA2 transfected with an HtrA2-specific siRNA in KF28 had not only cisplatin resistance, but also more invasive capacity than those with non-specific siRNA. Repeated treatment with cisplatin downregulated the HtrA2 protein, which led to cisplatin resistance and increased invasive capacity. Thus, HtrA2 might be a biomarker of response to cisplatin treatment and prognosis, after cisplatin-based chemotherapy.