TGF-β1 elevates P-gp and BCRP in hepatocellular carcinoma through HOTAIR/miR-145 axis

Multidrug resistance (MDR) is common in patients and has been linked to transforming growth factor-β1 (TGF-β1) and overexpression of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), although the molecular mechanisms remain largely unknown. This study aimed to investigate the mechanisms underlying TGF-β1-induced MDR in hepatocellular carcinoma (HCC) cells. It was found that TGF-β1 upregulated HOX transcript antisense RNA (HOTAIR) expression in HCC cells. When drosophila mothers against decapentaplegic 4 (SMAD4) was silenced, HOTAIR expression was accordingly reduced. Meanwhile, miR-145 expression was increased in the case HOTAIR was silenced. If the enhancer of zeste homolog 2 (EZH2) was knocked down using small interfering RNA (siRNA), miR-145 expression was decreased. Then, the regulatory role of miR-145 in P-gp and BCRP expression was explored. The results showed that the expression of P-gp and BCRP protein was suppressed by miR-145 through binding to the 3'-untranslated regions (3'-UTRs) of P-gp and BCRP. In conclusion, our study revealed a novel mechanism explaining TGF-β1-induced MDR in HCC through upregulating P-gp and BCRP via the SMAD4/HOTAIR/miR-145 axis.