Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). Since many HCC patients experience drug resistance, there is an urgent need to discover more effective therapeutic strategies to overcome drug resistance. Long non-coding RNAs (lncRNAs) play an important role in tumor drug resistance. However, research on the role of lncRNA H19 in sorafenib resistance in HCC is quite limited. In the present study, CCK-8 assay, RT-qPCR, EdU staining, immunofluorescence staining, and western blot analysis were used to detect the effect of lncRNA H19 on sorafenib resistance of HCC cells. H19 expression was found to be negatively related to sorafenib sensitivity in HCC cells. Knockdown of lncRNA H19 elevated sorafenib sensitivity by suppressing epithelial-mesenchymal transition (EMT) in HCC cells. H19 upregulated miR-675 expression. miR-675 inhibitor decreased the cell viability in sorafenib-treated HCC cells, while miR-675 overexpression had the opposite effect on the treated cells. When the cells were pretreated with miR-675 mimic, H19 siRNA did not alter the effect of miR-675 on sorafenib sensitivity. In conclusion, our study provides new clues for further clinical treatment of sorafenib-resistant liver cancer patients.
Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.
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