![]() ![]() Knowledgebase for rice sheath blight information (KRiShI) is a manually curated user-friendly knowledgebase for rice sheath blight (SB) disease that allows users to efficiently mine, visualize, search, benchmark, download, and update meaningful data and information related to SB using its easy and interactive interface. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation/migration and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas and hope for the precision therapy of HCC. Transwell assay found that both LZTR1 knockdown and KRAS knockdown can induce lenvatinib resistance in HCC cells. In lenvatinib resistance inducible experiment, upregulation of LZTR1 protein as well as downregulation of KRAS protein were detected in HCC cells exposed to gradient concentrations of lenvatinib for 48 h. In vitro experiments confirmed that LZTR1 knockdown promoted HCC cell proliferation and migration, and western blot and cycloheximide chase assay further demonstrated that LZTR1 induced KRAS ubiquitination and degradation, thereby inhibiting the RAS/RAF/MEK/ERK signaling. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly low expressed in HCC tissues and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. To explore the roles of LZTR1 in HCC progression and the potential mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Lenvatinib is the first-line drug for the treatment of advanced HCC, which has faced serious problem of drug resistance. However, it’s still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting such signaling pathway. LZTR1 is a substrate specific adaptor for E3 ligase involved in ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress tumor progression.
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