Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling
Ganghui Ye,
Jie Wang,
Jingyi Xia,
Chenlu Zhu,
Chaoyu Gu,
Xinming Li,
Jingyun Li,
Meng Ye,
Xiaofeng Jin
Affiliations
Ganghui Ye
Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China; Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
Jie Wang
Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China; Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
Jingyi Xia
Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center of Ningbo University, Ningbo, 315211, China
Chenlu Zhu
Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center of Ningbo University, Ningbo, 315211, China
Chaoyu Gu
Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
Xinming Li
Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
Jingyun Li
Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China; Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
Meng Ye
Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China; Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China; Corresponding author. Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China.
Xiaofeng Jin
Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China; Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China; Corresponding author. Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China.
LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying 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. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.
