Suppression of Annexin A11 in Ovarian Cancer: Implications in Chemoresistance

Ovarian cancer patients treated with cisplatin-based chemotherapy often develop acquired cisplatin resistance and, consequently, cancer recurrence. We have previously reported that annexin A11 is associated with cisplatin resistance and related to tumor recurrence in ovarian cancer patients. In this study, we used small interfering RNA to suppress annexin A11 expression in ovarian cancer cells followed by various in vitro assays. We showed that knockdown of annexin A11 expression reduced cell proliferation and colony formation ability of ovarian cancer cells. Epigenetic silencing of annexin A11 conferred cisplatin resistance to ovarian cancer cells. Through a comprehensive time course study of cisplatin response in ovarian cancer cells with/without suppression of annexin A11 expression using whole-genome oligonucleotide microarrays, we identified a set of differentially expressed genes associated with annexin A11 expression and some patterns of gene expressions in response to cisplatin exposure. These identified genes/patterns were further validated by real-time polymerase chain reaction and immunoblot analysis. Many of them such as HMOX1, TGFBI, LY6D, S100P, EIF4EBP2, DHRS2, and PCSK9 have been involved in apoptosis, cell cycling/proliferation, cell adhesion/migration, transcription regulation, and signal transduction. In addition, immunohistochemistry analyses indicated that annexin A11 immunointensity inversely correlated with HMOX1 immunoreactivity in 142 ovarian cancer patients. In contrast to annexin A11, HMOX1 immunoreactivity positively correlated with in vitro cisplatin resistance in ovarian cancers. Collectively, annexin A11 is directly involved in cell proliferation and cisplatin resistance of ovarian cancer. Manipulation of annexin A11 and its associated genes may represent a novel therapeutic strategy in human ovarian cancers.