The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma

Abstract

HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib-resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients’ samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients.

Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions

“…Remarkably, the delivery of a cholesterol modified agomiR-30a-5p in a mouse model of sorafenib resistant HCC, displayed anticancer effects, suggesting the adoption of a combined approach in sorafenib resistant settings. 69 To sum up, evidence supporting miRNAs involvement in sorafenib resistance in HCC are sound. Thus, miRNAs appear promising molecules to be validated as both biomarkers and therapeutic tools.…”

Regulatory Mechanisms of LncRNAs in Cancer Glycolysis: Facts and Perspectives

“…5 In hepatocellular carcinoma (HCC) cells, enhanced aerobic glycolysis promotes sorafenib-resistance, and suppression of glycolysis reverses this resistance. 26 Radiotherapy is also used to treat cancers. Radiation can kill cancer cells through breaking DNA double-strands and can thus prolong the survival of cancer patients and improve their quality of life.…”

The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma

“…MiR-30a-5p expression is decreased in HCC tissues, inhibits the PI3K/AKT axis, targets CLCF1, and then increases the sensitivity of HCC cells to sorafenib (20). MiR-375, which is also down-regulated in HCC, inhibits AKT activation by targeting AEG-1, suppresses tumor angiogenesis in HCC, and reverses the sorafenib resistance of HCC (31).…”