Upregulation of miR‐138 Increases Sensitivity to Cisplatin in Hepatocellular Carcinoma by Regulating EZH2

Abstract

Chemotherapeutic insensitivity is a major obstacle for effective treatment of hepatocellular carcinoma (HCC). Recently, new evidence showed that microRNAs (miRNAs) are closely related to drug sensitivity. This study aimed to investigate the relationship between miR-138 expression and cisplatin sensitivity of HCC cells by regulation of EZH2. CCK-8, EdU, and western blotting are determining the cell viability, proliferation, EZH2, and EMT-related protein expression. It was found that compared with normal samples, miR-138 expression was lower in cancer tissue; it was also downregulated in HCC cells. Transfected with miR-138 mimic increased sensitivity of HCC cells to cisplatin. Mechanistically, Luciferase Reporter analysis verified the interaction between miR-138 and target gene EZH2. Inhibition of EZH2 enhanced cisplatin sensitivity and transfection with EZH2 mimic mirrored the function of miR-138 in cisplatin sensitivity. Furthermore, the role of miR-138 on reversed cisplatin-induced epithelial–mesenchymal transition (EMT) was attenuated when combined with EZH2 plasmid. In conclusion, all data from this study illustrate that miR-138 may as a tumor suppressor provides a potential treatment method to treating HCC.

The long and short non-coding RNAs modulating EZH2 signaling in cancer

“…It has been reported that EMT induction can lead to cisplatin resistance [ 182 ]. MiRNA-138 reduces EZH2 expression to inhibit EMT, resulting in an increase in cisplatin sensitivity in hepatocellular carcinoma cells [ 183 ]. Overall, these studies agree with the fact that miRNA/EZH2 axis can affect proliferation, metastasis, and therapy response of hepatocellular carcinoma cells, and in this way, different molecular pathways such as Wnt, STAT3 and EMT are affected.…”

The interplay between noncoding RNAs and drug resistance in hepatocellular carcinoma: the big impact of little things

“…Furthermore, miR-651-3p can inhibit ATG3 [ 76 ] mediated cell autophagy to strengthen the susceptibility of HCC to cisplatin resistance [ 77 ]. Studies have revealed that miR-138-5p inhibits EZH2 and intensifies the sensitivity of HCC to cisplatin [ 78 ]. Likewise, the overexpression of miR-9 in HCC increases their sensitivity to cisplatin by preventing EMT and inhibiting EIF5A2.…”

Circular RNAs in hepatocellular carcinoma: Recent advances

“…Cisplatin resistance: Cisplatin is one of the few most common chemotherapy drugs used to treat HCC. However, thus far, the drug resistance of HCC cells during chemotherapy has been revealed to be the main factor affecting chemotherapy failure[ 110 , 111 ]. Therefore, how to control the occurrence of cisplatin resistance in HCC cells and improve drug sensitivity and therapeutic effects are critical to prolonging the survival of patients with advanced HCC.…”