Upregulation of microRNA‐135b and microRNA‐182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway

摘要

MicroRNAs (miRNAs) are increasingly involved in the development of drug resistance, including 5‐fluorouracil (5‐FU) resistance in colorectal cancer (CRC). Aberrant sialylation is correlated with human CRC. The study was to explore whether miR‐135b and miR‐182 modulated 5‐FU chemoresistance of CRC by targeting ST6GALNAC2 via PI3K/AKT pathway. MiR‐135b and miR‐182 were found to be up‐regulated in CRC tissues and 5‐FU resistant CRC cell lines. Forced miR‐135b and miR‐182 expression also affected ST6GALNAC2 levels. Using reporter‐gene assay, ST6GALNAC2 was identified as direct target of miR‐135b and miR‐182, while ST6GALNAC2 expression exhibited patterns opposite to that of miR‐135b and miR‐182 in CRC samples and cell lines. Interestingly, up‐regulation of miR‐135b or miR‐182 increased drug resistance and proliferation, but decreased apoptosis in 5‐FU resistant CRC cell lines. Suppression of these miRNAs implicated an inverse function, while altered expression of ST6GALNAC2 mediated CRC progression upon transfection with miR‐135b/‐182 mimic or inhibitor. Furthermore, miR‐135b and miR‐182 were clarified to regulate the activity of phosphoinositide‐3 kinase (PI3K)/AKT pathway. Inhibition of the PI3K/AKT pathway enhanced the chemosensitivity to 5‐FU in HCT‐8/5‐FU and LoVo/5‐FU. Taken together, miR‐135b and miR‐182 may reverse the resistance to 5‐FU in CRC cells by targeting ST6GALNAC2 via PI3K/AKT pathway, which render potential chemotherapy targets for the treatment of CRC.