miR-183-5p attenuates the effect of sorafenib on human hepatocellular carcinoma via inhibiting SOCS6/JAK2/STAT3 pathway

Abstract

Objective: MicroRNA plays a crucial role in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib (SOR). Elevation of miR-183-5p is associated with poor survival among patients with HCC. This study aimed to investigate the impact of miR-183-5p on SOR resistance in HCC as well as its related signaling pathway. The objective is to provide new insights, directions, and a theoretical basis for the clinical diagnosis and treatment of HCC. Design: Human normal hepatocytes (LO2) and HCC cell lines (HepG2, Huh7, and MHCC97H) were cultured, and were constructed with miR-183-5p inhibition and SOCS6 overexpression. Biotrust analysis and qRT-PCR were employed to assess the expression of miR-183-5p in liver cancer tissues or cells, respectively. Flow cytometry determined apoptosis rate in each group of cells, while CCK was used for detecting the 50% inhibitory concentration (IC50) of HCC followed SOR treatment. Western blotting was used to detect protein expression changes of SOCS6, p-JAK2, JAK2, p-STAT3, and STAT3. Results: Bioinformatics revealed significantly high expression of miR-183-5p in liver cancer compared to normal tissues. Consistent with this analysis, the expression of miR-183-5p was upregulated in human HCC cell lines, in order of Huh7, HepG2, and MHCC97H, compared to that of non-HCC cells. CCK-8 assays results shown that the IC50 value of sorafenib in Huh7 cells with higher expression levels of miR-183-5p were more high than Hep3B and MHCC97H cells with the relative lower expression levels of miR-183-5p. SOCS6 was elevated with the miR-183-5p inhibition compared to the control. Furthermore, the IC50 value of sorafenib was significantly decreased following miR-183-5p inhibition and increased in the miR-183-5p overexpression compared to the mock treatment. Conversely, the IC50 value of sorafenib in the SOCS6 overexpression group was significantly decreased compared to the control. Conclusions: Dysregulation of the miR-183-5p-SOCS6/JAK2/STAT3 axis plays a critical role in patients' responses to SOR treatment. Manipulation of this axis could potentially enhance the survival of patients with HCC, especially in the context of addressing drug resistance.