MicroRNA-mediated autophagic signaling networks and cancer chemoresistance

Abstract

Chemoresistance remains a major clinical obstacle to successful cancer treatment and brings about poor prognosis of the patients, yet the underlying mechanisms have not been entirely understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that may play an essential role for regulation of programmed cell death, which consists of apoptosis and autophagy. Autophagy refers to an evolutionarily conserved catabolic process in which, a cell degrades long-lived proteins and damaged organelles. Recently, increasing evidence indicates that autophagy is associated with multiple cancer-related pathways, including resistance to chemotherapeutics. Moreover, manipulation of miRNA expression levels may increase cell sensitivity to cytotoxic drugs through targeting the autophagic signaling pathway. In this review, we summarized the recent findings concerning miRNAs involved in autophagy, mainly focused on the mechanism of miRNA modulation at different autophagic stages, the crucial role of miRNAs in the interconnection between autophagy and apoptosis, and the potential of miRNAs to overcome chemoresistance by targeting autophagic pathways.

FIG. 1.

MicroRNAs (miRNAs) modulate different autophagic stages. MicroRNAs, consisting of oncogenic and tumor suppressive ones, can modulate different autophagic stages, mainly focus on several signaling pathways: (A) ULK1 complex; (B) PI3KCIII complex; (C) two ubiquitin-like conjugation pathways. (D) Other miRNAs such as miR-375, miR-221/222, and miR-519 are also involved in the autophagy process.

FIG. 2.

The emerging roles miRNAs played in cross talk between autophagy and apoptosis. In addition to targeting autophagy-associated proteins such as Atg4D, RAB5A, and LC3-II, miRNAs can also mediate the cross talk between autophagy and apoptosis via targeting the shared switch molecules such as Beclin-1, Atg5, and SQSTM1, and via changing the balance of nucleosomal histone acetylation.