miR-15a-5p enhances the malignant phenotypes of colorectal cancer cells through the STAT3/TWIST1 and PTEN/AKT signaling pathways by targeting SIRT4.

ABSTRACT

Colorectal cancer (CRC) continues to represent one of the major causes of cancer-related mortality and morbidity. MicroRNAs (miRNAs) are confirmed to be involved in modulating substential biological processes by affecting the expression of targeted genes, including carcinogenesis. In the present study, the expression pattern and functional roles of microRNA-15a-5p (miR-15a-5p) in CRC cells were investigated. The data from TCGA database indicated that miR-15a-5p is highly expressed in CRC tissues. Moreover, ectopic expression of miR-15a-5p facilitated the proliferation, migration, and invasion of CRC cells. Furthermore, bioinformatic analysis combinating with dual-luciferase assay revealed that SIRT4 acts as a crucial target of miR-15a-5p. Accordingly, overexpression of SIRT4 suppresses the miR-15a-5p-mediated enhancement in the proliferation, migration, and invasion of CRC cells, while the opposite phenotypes were observed after inhibition of SIRT4. Moreover, we further revealed that miR-15a-5p restrained the expression of SIRT4 to exacerbate the malignant phenotypes by modulating STAT3/TWIST1 and PETN/AKT signaling in CRC cells. Alternatively, inhibition of the miR-15a-5p/SIRT4 axis enhanced the chemosensitivity of 5-fluorouracil- and oxaliplatin-resistant HCT116 cells. Altogether, our evidence suggests that miR-15a-5p plays an essential role in promoting the proliferation, migration, and chemoresistance of CRC cells via targeting SIRT4 to modulate STAT3/TWIST1 and PETN/AKT signaling, which may serve as a promising therapeutic target for CRC therapy.