Hypoxia-induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway

Abstract

Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including cancer. Hypoxia induces upregulation of a specific set of microRNAs (miRNAs) in a variety of cell types. Here, we describe hypoxia-induced MIR155 as a potent inducer of autophagy. Enforced expression of MIR155 increases autophagic activity in human nasopharyngeal cancer and cervical cancer cells. Knocking down endogenous MIR155 inhibits hypoxia-induced autophagy. We demonstrated that MIR155 targets multiple players in MTOR signaling, including RHEB, RICTOR, and RPS6KB2. MIR155 suppresses target-gene expression by directly interacting with their 3′ untranslated regions (UTRs), mutations of the binding sites abolish their MIR155 responsiveness. Furthermore, by downregulating MTOR signaling, MIR155 also attenuates cell proliferation and induces G1/S cell cycle arrest. Collectively, these data present a new role for MIR155 as a key regulator of autophagy via dysregulation of MTOR pathway.

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

“…Several studies report an induction of miR‐155 expression after hypoxia35, 36 and following stroke 37, 38. Similar to our in vivo studies, the expression of miR‐155 was not significantly altered in HBMECs at 3 days after the in vitro hypoxia.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…BNIP3, another known HIF-1 target, has also been reported to facilitate the accumulation of the GDP-bound form of RHEB and the consequent down-regulation of mTOR in hypoxia [77]. In addition, the HIF-1-inducible miR-155 also targets elements of the mTOR pathway including RHEB, the mTORC2 member RICOR and the mTOR effector ribosomal protein S6KB2 [78]. Downregulation of these targets seemingly complements the effect of REDD1 and BNIP3 and may contribute to the limitation of the mTOR activity during hypoxia thereby forming a negative feedback loop via the mTOR and HIF pathways ( Figure 4A).…”

Autophagic program is regulated by miR-325

“…45 Enforced expression of miR-155 can increase autophagic activity in human nasopharyngeal cancer and cervical cancer cells, whereas knockdown of miR-155 can inhibit hypoxia-induced autophagy. 46 Autophagy is controlled by a complex interplay between the anti-and pro-autophagic proteins, [47][48][49][50] and more than 800 microRNAs have been identified. 51 The function of miR-325 remains unknown.…”