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.
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