Abstract
Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.
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Change history
07 September 2020
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
The authors thank Prof. Hua Jiang (State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine) for the generous gift of the EGFR plasmid used in this study.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81972581, 81472570), the National Key Sci-Tech Special Project of China (2018ZX10723204–006), Natural Science Foundation of Shanghai (19ZR1452800), Foundation of Shanghai Municipal Health Commission (201940429) and the SKLORG Research Foundation (91-17-29).
Author contributions
HT designed the research. QQZ, TTH, ZYJ, CG, XXC, LLZ, FYZ, and MXZ performed the experiments. TYC, YC, HL, MY, and JJL provided technical assistance. HT wrote the paper. All authors read and approved the final paper.
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Zhou, Q., Huang, T., Jiang, Z. et al. Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway. Oncogene 39, 2140–2155 (2020). https://doi.org/10.1038/s41388-019-1131-9
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DOI: https://doi.org/10.1038/s41388-019-1131-9
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