A positive feedback loop between miR-181b and STAT3 that affects Warburg effect in colon cancer via regulating PIAS3 expression

Abstract

This study aimed to investigate the relationship between the expression of microRNA (miR)-181b, protein inhibitor of activated STAT3 (PIAS3) and STAT3, and to examine the function of the miR-181b/PIAS3/STAT3 axis on the Warburg effect and xenograft tumour growth of colon cancer. Moreover, a positive feedback loop between miR-181b and STAT3 that regulated the Warburg effect in colon cancer was explored. A luciferase reporter assay was used to identify whether PIAS3 was a direct target of miR-181b. The gain-of-function and loss-of-function experiments were performed on HCT 116 cells to investigate the effect of miR-181b/PIAS3/STAT3 on the Warburg effect and xenograft tumour growth of colon cancer, as determined by commercial kits and xenograft experiments. The relationship between the expression of miR-181b, PIAS3 and STAT3 in HCT 116 and HT-29 cells was determined using RT-qPCR and Western blot. We found miR-181b was a direct regulator of PIAS3. miR-181b promoted the Warburg effect and the growth of colon cancer xenografts; however, these effects could be reversed by PIAS3. miR-181b expression interacted with STAT3 phosphorylation in a positive feedback loop in colon cancer cells via regulating PIAS3 expression. In conclusion, this study for the first time demonstrated that miR-181b contributed to the Warburg effect and xenograft tumour growth of colon cancer by targeting PIAS3. Moreover, a positive feedback loop between miR-181b and STAT3 that regulated the Warburg effect in colon cancer was also demonstrated. This study suggested miR-181b/PIAS3/STAT3 axis as a novel target for colon cancer treatment.

Keywords: MicroRNA-181b; PIAS3; STAT3; Warburg effect; positive feedback loop.