Modulation of hypoxia-signaling pathways by extracellular long non-coding RNA regulator of reprogramming

Abstract

Resistance to adverse environmental conditions such as hypoxia contributes to the efficacy of anticancer therapies and tumor progression. Although deregulated expression of many long non-coding RNA (lncRNA) occur in human cancers, their contributions to tumor responses to hypoxia are unknown. RNA expression profiling identified several hypoxia-responsive lncRNAs including linc-RoR, which is also increased in expression in malignant liver cancer cells. Linc-RoR expression was increased in hypoxic regions within tumor cell xenografts in vivo. Tumor cell viability during hypoxia was reduced by siRNA to linc-RoR. Compared to controls, siRNA to linc-RoR decreased p70S6K1 phosphorylation, PDK1 and HIF-1α protein expression, and increased expression of the linc-RoR target miR-145. Linc-RoR was highly expressed in extracellular RNA released by HCC cells during hypoxia. Incubation with extracellular vesicle preparations containing extracellular RNA increased linc-RoR, HIF-1α expression and cell survival in recipient cells. These studies show that lncRNA-RoR is a hypoxia-responsive lncRNA that is functionally linked to hypoxia signaling in HCC through a miR-145/HIF-1α signaling module, and identify a mechanistic role of inter-cellular extracellular transfer of linc-RoR in promoting cell survival during hypoxic stress.