Knockdown Increases the Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib by Disrupting miR-145-5p/HK2 Axis-Mediated Mitochondrial Function and Glycolysis.

BACKGROUND

Frequent drug resistance seriously limits the therapeutic efficacy of sorafenib in advanced hepatocellular carcinoma (HCC). Strategies to increase the response to sorafenib are limited, and the underlying mechanism to facilitate such an increase is not entirely understood. Homeobox (HOX) transcript antisense intergenic RNA () expression is high in HCC, promoting the occurrence and progression of HCC. In this study, we explored the mechanism through which knockdown affects the response of HCC cells to the chemotherapeutic sorafenib.

METHODS

Cell viability and apoptosis were assessed using MTT assay, flow cytometry, and nuclear staining. Mitochondrial function and isolation were determined using flow cytometry and a mitochondrial isolation kit. Glycolysis was measured by glucose and lactic acid assay kits. The underlying mechanisms were explored through western blotting, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation (ChIP).

RESULTS

knockdown increased sorafenib-induced apoptosis in the HCC cells. and hexokinase 2 () expression levels were upregulated in human HCC tissues, demonstrating a significant correlation. The knockdown of or aggravated mitochondrial dysfunction and inhibited glycolysis. Further, knockdown promoted sorafenib-mediated mRNA downregulation, resulting in decreased HK2 protein levels in cells and mitochondria. This ultimately facilitated the mitochondrial apoptotic pathway. Moreover, it was demonstrated that regulated HK2 via polycomb repressive complex 2 (PRC2)-mediated epigenetic modification of miR-145-5p in HCC.

CONCLUSIONS

knockdown increased the sensitivity of HCC cells to sorafenib by disrupting the miR-145-5p/HK2 axis-mediated mitochondrial function and glycolysis, suggesting new strategies for HCC treatment.