Long non-coding RNA ANRIL promotes chemoresistance in triple-negative breast cancer via enhancing aerobic glycolysis

摘要

Aims: lncRNA ANRIL expression is dysregulated in many human cancers and is thus a useful prognostic marker for cancer patients. However, whether ANRIL is involved in drug resistance in triple-negative breast cancer (TNBC) has not yet been investigated. Main methods: A luciferase reporter assay was conducted to verify the binding between miR-125a and ANRIL. RT-PCR and western blotting were performed to detect the expression of miR-125a, ANRIL, and ENO1. Glycolysis stress was assessed using the Seahorse extracellular flux analyzer. Functional studies were performed using both in vitro and in vivo xenograft models. Key findings: ANRIL was markedly upregulated in both patients with TNBC and TNBC cell lines. Knockdown of ANRIL increased the cytotoxic effect of ADR and repressed cellular glycolytic activity in TNBC cells. Mechanistic analysis showed that ANRIL may act as a competing endogenous RNA of miR-125a to relieve the repressive effect of miR-125a on its target glycolytic enzyme enolase (ENO1). Notably, 2-deoxy-glucose attenuated ANRIL-induced increase in drug resistance in TNBC cells. Significance: These results indicate that knockdown of ANRIL plays an active role in overcoming drug resistance in TNBC by inhibiting glycolysis through the miR-125a/ENO1 pathway, which may be useful for the develop-ment of novel therapeutic targets for treating patients with TNBC, especially those with drug resistance.

关键词