Upregulated UCA1 contributes to oxaliplatin resistance of hepatocellular carcinoma through inhibition of miR‐138‐5p and activation of AKT/mTOR signaling pathway

Abstract

Abstract Hepatocellular carcinoma (HCC) inevitably developed oxaliplatin (OXA) resistance after long‐term treatment, but the mechanism remains unclear. Here, we found that LncRNA UCA1 was upregulated in most of OXA‐resistant HCC tissues and cells (HepG2/OXA and SMMC‐7721/OXA). Follow‐up analysis and online Kaplan–Meier Plotter revealed that HCC patients with high UCA1 level had a shorter survival compared with those with low expression. Overexpression of UCA1 increased OXA IC50 in HepG2 and SMMC‐7721 cells, whereas knockdown of UCA1 decreased OXA IC50 in resistant counterparts. Moreover, dual luciferase reporter assay showed that co‐transfection of UCA1‐WT plasmid with miR‐138‐5p mimics enhanced fluorescence signals, whereas co‐transfection of UCA1‐Mut plasmid and miR‐138‐5p mimics did not induce any changes. Consistently, UCA1 levels in HepG2/OXA and SMMC‐7721/OXA cells were downregulated after transfected with miR‐138‐5p mimics. UCA1 silencing or transfection of miR‐138‐5p mmics inhibited the activation of AKT and mTOR in HepG2/OXA and SMMC‐7721/OXA cells, whereas UCA1 overexpression increased the phosphorylated AKT and mTOR levels in parental counterparts. Rapamycin or miR‐138‐5p mimics similarly suppressed the activation of AKT and mTOR, whereas UCA1 overexpression exert opposite roles. Interestingly, administration of rapamycin or miR‐138‐5p mimics apparently antagonized the effects of UCA1 on AKT and mTOR activation. Besides, depletion of UCA1 triggered more dramatic regression of HepG2 xenografts than that of HepG2/OXA xenografts with OXA treatment and impaired the p‐AKT and p‐mTOR levels in vivo. In conclusion, our findings provide the evidence that UCA1 may contribute to OXA resistance via miR‐138‐5p‐mediated AK /mTOR activation, suggesting that UCA1 is a potential therapeutic target for HCC.

Keywords

• hepatocellular carcinoma
• long noncoding RNA
• miR‐138‐5p
• oxaliplatin resistance
• UCA1