HIF2A overexpression reduces cisplatin sensitivity in cervical cancer by inducing excessive autophagy

Hypoxia-induced autophagy is a crucial factor that induces chemotherapy resistance in tumor cells. As a key regulator facilitating the adaptation of solid tumors to hypoxia, the role of hypoxia-inducible factors (HIFs) in regulating hypoxia-induced chemotherapy resistance and autophagy has been extensively studied. However, the majority of studies have mainly focused on HIF-1. Direct evidence concerning the role of HIF2A in cisplatin resistance is sparse, and its underlying mechanism is not yet known.

Animal models were constructed by subcutaneously injecting cervical cancer cells stably overexpressing HIF2A (LV-HIF2A) with or without intraperitoneal injection of cisplatin. Tumor size and weight were evaluated to determine tumor growth. Apoptosis was detected by TUNEL assay and protein expression by western blotting.

Nude mice injected with cells overexpressing HIF2A showed larger and heavier tumors than those in mice injected with negative control lentivirus (LV-NC)-infected cells, with or without cisplatin. Fewer apoptotic cells were noted in tumor tissues from the LV-HIF2A group than from the LV-NC group, with or without cisplatin. Additionally, expression of the anti-apoptotic protein, B-cell lymphoma 2 (BCL2), and autophagy-related proteins, beclin 1 and autophagy related 5 (ATG5), were found to be higher in the LV-HIF2A group than in the LV-NC group, regardless of cisplatin treatment. Moreover, expression of the pro-apoptotic protein, BCL2-associated X (BAX), was lower in tumor tissues from the LV-HIF2A group than from the LV-NC group. Effect of HIF2A overexpression on cisplatin sensitivity was found to be alleviated in vivo by the autophagy inhibitor, 3-methyladenine (3-MA).

HIF2A overexpression promoted tumor growth and autophagy but suppressed apoptosis in vivo, with or without cisplatin. The HIF2A overexpression-affected cisplatin sensitivity was alleviated by 3-MA. Therefore, we suggest that HIF2A overexpression reduces cisplatin sensitivity in cervical cancer by inducing excessive autophagy.