MicroRNAs as regulators and mediators of forkhead box transcription factors function in human cancers

Abstract

Evidence has shown that microRNAs are widely implicated as indispensable components of tumor suppressive and oncogenic pathways in human cancers. Thus, identification of microRNA targets and their relevant pathways will contribute to the development of microRNA-based therapeutics. The forkhead box transcription factors regulate numerous processes including cell cycle progression, metabolism, metastasis and angiogenesis, thereby facilitating tumor initiation and progression. A complex network of protein and non-coding RNAs mediates the expression and activity of forkhead box transcription factors. In this review, we summarize the current knowledge and concepts concerning the involvement of microRNAs and forkhead box transcription factors and describe the roles of microRNAs-forkhead box axis in various disease states including tumor initiation and progression. Additionally, we describe some of the technical challenges in the use of the microRNA-forkhead box signaling pathway in cancer treatment.

Keywords: cancer; forkhead box transcription factor; microRNA; post-transcriptional regulation.

Figure 1. Structural organization of the FOX family

A. Three-dimensional structure of the DNA-binding domain of FOXO4, showing helical (H) sections, β-strand(S) sections and winged (W) sections [8]. B. Schematic diagram of primary structures of different FOX proteins. ID, inhibitory domain; LZ, leucine zipper; NES, nuclearexport sequence; NLS, nuclear localization sequence; NRD, N-terminal repressor domain; TAD, transactivation domain; TRD, transcriptional repressor domain.

Figure 2. Schematic representation of the FOX regulating miRNAs signaling pathways

A. TXNIP/miR-124a/FoxA2/IAPP; B. miR-204/MEIS2-FOXC1/PAX6/ITGβ1; C. resveratrol/miRNA-520h/PP2A/C/Akt/NF-κB/FOXC2; D. Gα12/AP-1/miR-135b/FOXO1-Gα12/miR-194/MDM2/FOXO1; E. miR-22-miR-486/PTEN/PI3K/AKT/FOXO1; F. TGF-β/FOXO1/miR-21/AKT/NF-KB/Snail; G. AR/PI3K/AKT/FOXO3/AP-1/miR-21/PTEN; H. miR-34a-146b-132-21-217/Sirt/FOXO1.