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NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis.

ABSTRACT: Recent studies have shown that long non-coding RNAs (lncRNAs) play a pivotal role in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, the biological action and potential mechanism of liver cancer cell drug resistance have not been clearly clarified. In this study, lncRNAs were screened and differentially expressed in parental and cisplatin-resistant cell lines (HepG2 and HepG2/CDDP). A novel lncRNA, termed NRAL (Nrf2 regulation-associated lncRNA), was identified, and the initial results indicated that it was highly expressed in HepG2 cisplatin resistant cell lines compared to their parental counterparts. Functionally, NRAL depletion significantly enhanced CDDP-mediated cytotoxicity and apoptosis in two cisplatin-resistant HCC cell lines. Mechanistically, the results indicated that NRAL regulates Nrf2 expression through miR-340-5p serving as a competing endogenous RNA (ceRNA), thus influencing the CDDP-induced phenotype in HCC. Collectively, the present investigation suggest that the NRAL/miR-340-5p/Nrf2 axis mediates cisplatin resistance in HCC, which may provide novel targets for overcoming cisplatin resistance in hepatocellular carcinoma cells.

SUBMITTER: Wu LL

PROVIDER: S-EPMC6381379 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis.

Wu Li-Li LL Cai Wen-Pin WP Lei Xin X Shi Ke-Qing KQ Lin Xiang-Yang XY Shi Liang L

Journal of cell communication and signaling 20180720 1

Recent studies have shown that long non-coding RNAs (lncRNAs) play a pivotal role in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, the biological action and potential mechanism of liver cancer cell drug resistance have not been clearly clarified. In this study, lncRNAs were screened and differentially expressed in parental and cisplatin-resistant cell lines (HepG2 and HepG2/CDDP). A novel lncRNA, termed NRAL (Nrf2 regulation-associated lncRNA), was identified, and ...[more]

PMID: 30030687

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Project description: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.

Project description:BackgroundDrug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified.MethodsThe clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets.ResultsWe found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3'-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response.ConclusionOur study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

Dataset Information

NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis.

Publications

NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis.

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