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.
Highlights
On a global scale, HCC ranks sixth among cancers and is the third leading cause of death due to cancer[1]
We further found that CLCF1 acts as a key mediator to orchestrate sorafenib resistance and aerobic glycolysis in HCC cells
Our findings reveal that the miR30a-5p/CLCF1/PI3K/AKT regulatory cascade is part of an important mechanism of sorafenib resistance and aerobic glycolysis in HCC cells, suggesting that miR30a-5p is a promising therapeutic target to reverse sorafenib resistance in HCC
Summary
HCC (hepatocellular carcinoma) ranks sixth among cancers and is the third leading cause of death due to cancer[1]. The incidence of this deadly disease is still on the rise, and curative treatments, For HCC treatment, conventional chemotherapeutics such as doxorubicin and fluorouracil are not efficacious and exhibit potent side effects[7,8]. Zhang et al Cell Death and Disease (2020)11:902 the treatment of HCC in patients who cannot undergo surgery is sorafenib. HCC exhibits notable resistance to sorafenib, and only one-third of patients with HCC at an advanced stage respond to treatment[11,15]. The results of multiple random clinical cases were systematically analyzed and revealed an increase in the survival time by only 3 months, indicating the urgent need to discover more robust molecular targeted drugs against drug-resistant tumors and to further conduct in-depth evaluation of the HCC resistance mechanism and improve the sensitivity of HCC to sorafenib
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