MiR-181b Controls Glycolysis As STAT3Activator In Colon Cancer Cells Through A Positive Feedback Loop

Cancer cells preferentially metabolize glucose through aerobic glycolysis. Thisphenomenon, known as the Warburg effect, is an anomalous characteristic of glucosemetabolism in cancer cells. The hallmark of tumor metabolism, Warburg effect existsin most cancer cells. In recent years, several studies have attempted to elucidate themechanisms responsible for Warburg effect. However, the complete picture remainselusive. MicroRNAs (miRNAs) are short noncoding RNAs,18to25nucleotides inlength, which regulate gene expression. They demonstrate complementarity with3’UTR (3’-untranslated region) of their target mRNAs. The miRNA-mediatedregulation of gene expression could be either by post-transcriptional regulation ofgene expression leading to target mRNA degradation or repression of its translationwith consequent decrease in the particular protein levels or even by upregulation ofthe targets. miRNAs regulate a vast majority of oncogenes and tumor suppressorgenes. Changes in the miRNA expressions and consequent alterations in signalingnetworks have been observed in a variety of human cancers. Multiple studies haverevealed that the altered metabolic pathways in cancers are tightly regulated bymiRNAs. The downstream targets of a number miRNAs are directly or indirectlyconnected to the metabolic regulation. However, the precise mechanisms aboutmiRNAs regulate Warburg effect is not well elucidated. Here, we explored itspotential role in cancer metabolism.In this work, we show that PIAS3(protein inhibitor of activated STAT3) is thetarget of miR-181b, and a significant inverse correlation between miR-181b andPIAS3mRNA levels in human colon tumors. We demonstrate that miR-181b down-regulates PIAS3and elevates STAT3(signal transducers and activators oftranscription3) activation. Base on STAT3activation has been reported could promote the transcription and expression of mir-181b-1, therefore, our results supporta positive feedback loop as a mechanism for persistent STAT3activation, in whichmiR-181b represses PIAS3to elevate STAT3activity, which in turn elevates miR-181b expression by promoting mir-181b-1transcription. Moreover, miR-181binhibition or PIAS3up-regulation in colon cancer cell lead to reduce glycolysis,proliferation and engraft tumour growth. In addition, PIAS3inhibition could abolishthe effect of miR-181b inhibition on colon cancer cell.We found that:(1) PIAS3is the direct target of miR-181b;(2) Inversecorrelation of miR-181b and PIAS3mRNA expression in human colon tumors;(3)miR-181b contributes to persistent STAT3activation though a positive feedback loopin colon cancer cells;(4) miR-181b regulates the glycolysis of colon cancer cell bytargeting PIAS3;(5) miR-181b regulates the proliferation and engraft tumour growthof colon cancer cell by targeting PIAS3.