HIF2A as a prognostic and clinical therapeutic target in ovarian clear cell carcinoma

Abstract

Ovarian clear cell carcinoma (CCC) is an aggressive subtype of ovarian cancer that is resistant to conventional chemotherapy, resulting in poor prognosis. CCC develops from endometriosis, which exposes tumor cells to a hypoxic microenvironment, thereby highlighting the critical role of hypoxia in ovarian CCC progression. Thus, identifying novel therapeutic targets, particularly those associated with hypoxia, is important. Hypoxia-inducible factor 2A (HIF2A) is a key regulator of hypoxic responses, but its role in ovarian CCC remains unclear. This study assessed the prognostic and functional significance of HIF2A in ovarian CCC and investigated its potential as a therapeutic target. Inhibiting HIF2A significantly suppressed ovarian CCC tumor growth through a genetic knockdown cell line as well as pharmacological inhibition using a novel HIF2A inhibitor, NKT2152. In vitro experiments showed that HIF2A suppression enhanced mitochondrial respiration and increased mitochondrial reactive oxygen species production alongside the downregulation of HIF2A target genes. Moreover, treatment with NKT2152 significantly reduced tumor growth in both cell line-derived and patient-derived xenograft models. In conclusion, our findings provide novel insights into the prognostic and functional role of HIF2A in ovarian CCC and underscore its potential as a promising therapeutic target.

Keywords: hypoxia‐inducible factor 2 a; mitochondria; ovarian clear cell carcinoma; oxidative stress.