Hypoxia-induced lncRNA ANRIL promotes cisplatin resistance in retinoblastoma cells through regulating ABCG2 expression.

Abstract

Cisplatin (DDP) resistance limits its efficacy for retinoblastoma (Rb). Hypoxia-inducible factor-1α (HIF-1α) has been shown to contribute to chemotherapy resistance in tumours under hypoxic conditions. This study was designed to explore the role and mechanism of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) in regulating DDP resistance in Rb cells under hypoxia and to validate whether HIF-1α was involved in this process. The interaction between HIF-1α and the promoter of ANRIL was analyzed using ChIP assay. Cell proliferation and apoptosis, as well as protein levels of drug resistance-related proteins (ABCG2 and MDR1) were examined to evaluate DDP resistance in Rb cells. The interactions between miR-328 and ANRIL as well as miR-328 and ABCG2 were analyzed using dual-luciferase reporter assays. Upon hypoxia, HIF-1α directly bound to the ANRIL promoter region to transcriptionally activate ANRIL. The hypoxia-induced ANRIL promoted Rb cell resistance to DDP, as evidenced by facilitation of cell proliferation, inhibition of cell apoptosis and upregulation of ABCG2 and MDR1. Mechanistically, ANRIL promoted Rb cell resistance to DDP by acting as a sponge of miR-328 to upregulate expression of ABCG2, which was confirmed as a direct target of miR-328. Collectively, hypoxia-induced ANRIL promotes DDP resistance in Rb cells by sponging miR-328 to upregulate ABCG2 expression.