Interplay between microRNAs and the STAT3 signaling pathway in human cancers

Abstract

MicroRNAs (miRNAs, also miR) are a class of noncoding endogenous RNAs that regulate gene expression through binding to protein-coding messenger RNA (mRNA) molecules, predominantly within the 3′-untranslated region (3′-UTR). Signal transducer and activator of transcription 3 ( STAT3) is a transcription factor that regulates a battery of genes involved in regulating a variety of biological processes. There is a growing body of evidence demonstrating that miRNAs are closely associated with the STAT3 signaling pathway. In this review, we focus on interactions between miRNAs and the STAT3 signaling pathway, focusing on their reciprocal regulation and roles in cancer. For instance, several papers independently support the existence of regulatory feedback loops between miRNAs and the STAT3 pathway in different cancer contexts including IL-6-STAT3-miR-24/miR-629-HNF4α-miR-124 and IL-6R-STAT3-NF-κB-Lin-28-let-7a. Furthermore, several miRNA components are reported to be involved in STAT3-mediated tumorigenesis, for example miR-21, miR-155, and miR-181b. Through binding to STAT3-binding sites within the promoters of these oncomiRs, STAT3 activates their transcription and mediates tumorigenesis. Some miRNAs directly modulate STAT3 activity through targeting the STAT3 3′-UTR; other miRNAs target SOCS, PIAS3, and EGFR genes, which encode proteins that regulate the STAT3 signaling pathway. Given that miRNAs represent a newly discovered class of regulatory molecules, investigating their biological functions and contribution to pathologies caused by STAT3 dysregulation is essential to improve our understanding of tumorigenesis and to develop novel anticancer therapeutics. The more we can learn about miRNAs- STAT3 interactions, the better able we will be to manipulate them for developing cancer therapeutics.