Lenvatinib is approved as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), however, its clinical efficacy is frequently limited by the emergence of drug resistance. This study aimed to elucidate the underlying mechanisms by which HCC develops resistance to lenvatinib. Lenvatinib-resistant HCC cell lines were established and subjected to RNA sequencing (RNA-seq) to identify genes associated with drug resistance. HCC cell lines stably overexpressing the p53 R280S mutation were constructed via lentiviral transduction. The effects of p53 R280S on HCC cell proliferation, apoptotic, and lenvatinib sensitivity were evaluated using Cell Counting Kit-8 (CCK-8) assays, flow cytometry, colony formation assays, TUNEL staining, and a mouse subcutaneous xenograft model. The underlying molecular mechanisms were further investigated by Western blotting, immunohistochemical staining (IHC), and quantitative real-time PCR (qRT-PCR). RNA sequencing of lenvatinib-resistant HCC cell lines revealed p53 dysregulation, and sanger sequencing identified the p53 R280S missense mutation, which was shown to enhance lenvatinib resistance in vitro and in vivo. The p53 R280S mutant attenuated lenvatinib-induced apoptosis. Furthermore, mutant p53 upregulated Bcl-2 expression and downregulated BAX expression, thereby suppressing apoptotic signaling. The p53 R280S mutation promotes lenvatinib resistance in HCC by inhibiting apoptosis.
Niangmei Cheng, Kexin Liu, Xin Qi et al.· Molecular and Cellular Bioch...· 0 citations
Hepatocellular carcinoma is one of the most common malignant tumors with poor clinical outcomes. Increasing numbers of long noncoding RNAs have been shown to be involved in the carcinogenesis and progression of HCC. However, the expressions, clinical significances, and roles of most lncRNAs in HCC are still unknown. In clinical samples, we utilized qPCR assays to measure the expression level of lncRNA MKRN3-AS1 in hepatocellular carcinoma (HCC) tissues compared with normal/adjacent tissues and analyzed its correlation with patient prognosis. Gain-of-function and loss-of-function experiments were performed in HCC cells to examine the effects of lncRNA MKRN3-AS1 on cell migration, invasion, and autophagy. For mechanistic investigation, bioinformatics analysis and molecular biology experiments were employed to verify the role of MKRN3-AS1 as a competitive endogenous RNA. Additionally, a mouse metastatic tumor model was established via tail vein injection to observe the impact of MKRN3-AS1 on lung metastasis of hepatocellular carcinoma. We found that lncRNA MKRN3-AS1 was dramatically upregulated in HCC tissues and associated with poor prognosis. Functionally, lncRNA MKRN3-AS1 promoted migration, invasion and autophagy of HCC cells. Mechanistically, MKRN3-AS1 acted as a "molecular sponge" for multiple miRNAs. By targeting miR-601, MKRN3-AS1 upregulate the expression of ZEB1, which directly promoted the invasion and migration of HCC cells. In addition, MKRN3-AS1 promoted autophagy via the miR-4487/ULK1 and miR-6881-3p/ATG5-ATG7 axes, which may enhance the stemness of HCC cells and thereby indirectly facilitate tumor invasion and migration. In mouse model, over-expression of MKRN3-AS1 facilitated lung metastasis of HCC. Collectively, The oncogenic function of MKRN3-AS1 in hepatocellular carcinoma may be attributed to its regulation of the miR-601/ZEB1, miR-4487/ULK1, and miR-6881-3p/ATG5-ATG7 signaling axes. Our findings suggest that MKRN3-AS1 may be a potential prognostic biomarker and therapeutic target for HCC.
Fei Wang, Ji-Zhe Liu, Gaoxiong Wang et al.· Scientific Reports· 0 citations
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