Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway

Oncogene volume 39, pages 2140–2155 (2020)Cite this article

Subjects

A Correction to this article was published on 07 September 2020

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SNX5 is often upregulated in HCC and is associated with poor prognosis in HCC patients.
Fig. 2: SNX5 increases HCC cell proliferation.
Fig. 3: Knockdown of SNX5 induces the G1/S phase arrest of HCC cells.
Fig. 4: SNX5 increases HCC cell metastasis.
Fig. 5: SNX5 enhances EGFR phosphorylation and signaling.
Fig. 6: SNX5 influences EGFR endosomal trafficking.
Fig. 7: SNX5 increases HCC cell proliferation, migration, and invasion by regulating the EGFR/ERK pathway.

Similar content being viewed by others

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.

References

  1. Villanueva A. Hepatocellular carcinoma. N. Engl J Med. 2019;380:1450–62.

    Article  CAS  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Google Scholar 

  3. Fu J, Wang H. Precision diagnosis and treatment of liver cancer in China. Cancer Lett. 2018;412:283–8.

    Article  CAS  Google Scholar 

  4. Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene. 2009;28(Suppl 1):S32–7.

    Article  CAS  Google Scholar 

  5. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37(Suppl 4):S9–15.

    Article  CAS  Google Scholar 

  6. Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16:972–7.

    Article  CAS  Google Scholar 

  7. Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S, Lauwers GY, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology. 2014;59:1577–90.

    Article  CAS  Google Scholar 

  8. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N. Engl J Med. 2008;358:1160–74.

    Article  CAS  Google Scholar 

  9. Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559–66.

    Article  CAS  Google Scholar 

  10. Heucken N, Ivanov R. The retromer, sorting nexins and the plant endomembrane protein trafficking. J Cell Sci. 2018;131:pii: jcs203695.

  11. Cullen PJ, Korswagen HC. Sorting nexins provide diversity for retromer-dependent trafficking events. Nat Cell Biol. 2011;14:29–37.

    Article  Google Scholar 

  12. Zhang S, Hu B, You Y, Yang Z, Liu L, Tang H, et al. Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21(Cip1/WAF1). Cancer Lett. 2018;419:116–27.

    Article  CAS  Google Scholar 

  13. Tanigawa K, Maekawa M, Kiyoi T, Nakayama J, Kitazawa R, Kitazawa S, et al. SNX9 determines the surface levels of integrin beta1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9. J Cell Physiol. 2019;234:17280–94.

  14. Bendris N, Stearns CJ, Reis CR, Rodriguez-Canales J, Liu H, Witkiewicz AW, et al. Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells. J Cell Sci. 2016;129:2804–16.

    Article  CAS  Google Scholar 

  15. Hu P, Liang Y, Hu Q, Wang H, Cai Z, He J, et al. SNX6 predicts poor prognosis and contributes to the metastasis of pancreatic cancer cells via activating epithelial-mesenchymal transition. Acta Biochim Biophys Sin (Shanghai). 2018;50:1075–84.

    Article  CAS  Google Scholar 

  16. Ara S, Kikuchi T, Matsumiya H, Kojima T, Kubo T, Ye RC, et al. Sorting nexin 5 of a new diagnostic marker of papillary thyroid carcinoma regulates Caspase-2. Cancer Sci. 2012;103:1356–62.

    Article  CAS  Google Scholar 

  17. Jitsukawa S, Kamekura R, Kawata K, Ito F, Sato A, Matsumiya H, et al. Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression. J Pathol. 2017;243:342–53.

    Article  CAS  Google Scholar 

  18. Bokel C, Brand M. Endocytosis and signaling during development. Cold Spring Harb Perspect Biol. 2014;6:a017020.

  19. Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003;422:37–44.

    Article  CAS  Google Scholar 

  20. Kaksonen M, Roux A. Mechanisms of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2018;19:313–26.

    Article  CAS  Google Scholar 

  21. Wang LH, Rothberg KG, Anderson RG. Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol. 1993;123:1107–17.

    Article  CAS  Google Scholar 

  22. Nothwehr SF, Ha SA, Bruinsma P. Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p. J Cell Biol. 2000;151:297–310.

    Article  CAS  Google Scholar 

  23. Nothwehr SF, Bruinsma P, Strawn LA. Distinct domains within Vps35p mediate the retrieval of two different cargo proteins from the yeast prevacuolar/endosomal compartment. Mol Biol Cell. 1999;10:875–90.

    Article  CAS  Google Scholar 

  24. Choi E, Kikuchi S, Gao H, Brodzik K, Nassour I, Yopp A, et al. Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. Nat Commun. 2019;10:1473.

    Article  Google Scholar 

  25. Brunt L, Scholpp S. The function of endocytosis in Wnt signaling. Cell Mol Life Sci. 2018;75:785–95.

    Article  CAS  Google Scholar 

  26. Kim N, Kim S, Nahm M, Kopke D, Kim J, Cho E, et al. BMP-dependent synaptic development requires Abi-Abl-Rac signaling of BMP receptor macropinocytosis. Nat Commun. 2019;10:684.

    Article  CAS  Google Scholar 

  27. Mosesson Y, Mills GB, Yarden Y. Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer. 2008;8:835–50.

    Article  CAS  Google Scholar 

  28. Menard JA, Christianson HC, Kucharzewska P, Bourseau-Guilmain E, Svensson KJ, Lindqvist E, et al. Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis. Cancer Res. 2016;76:4828–40.

    Article  CAS  Google Scholar 

  29. Joffre C, Barrow R, Menard L, Calleja V, Hart IR, Kermorgant S. A direct role for Met endocytosis in tumorigenesis. Nat Cell Biol. 2011;13:827–37.

    Article  CAS  Google Scholar 

  30. Xu MJ, Johnson DE, Grandis JR. EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017;36:463–73.

    Article  Google Scholar 

  31. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12:3–20.

    Article  Google Scholar 

  32. Liu H, Liu ZQ, Chen CX, Magill S, Jiang Y, Liu YJ. Inhibitory regulation of EGF receptor degradation by sorting nexin 5. Biochem Biophys Res Commun. 2006;342:537–46.

    Article  CAS  Google Scholar 

  33. Sun Y, Hedman AC, Tan X, Schill NJ, Anderson RA. Endosomal type Igamma PIP 5-kinase controls EGF receptor lysosomal sorting. Dev Cell. 2013;25:144–55.

    Article  CAS  Google Scholar 

  34. Liu Z, Chen D, Ning F, Du J, Wang H. EGF is highly expressed in hepatocellular carcinoma (HCC) and promotes motility of HCC cells via fibronectin. J Cell Biochem. 2018;119:4170–83.

    Article  CAS  Google Scholar 

  35. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  36. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharm Res. 2019;144:19–50.

    Article  CAS  Google Scholar 

  37. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.

    Article  CAS  Google Scholar 

  38. Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140:1410–26.

    Article  CAS  Google Scholar 

  39. Jiang Z, Zhou Q, Ge C, Yang J, Li H, Chen T, et al. Rpn10 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through the PTEN/Akt signaling pathway in hepatocellular carcinoma. Cancer Lett. 2019;447:1–11.

    Article  CAS  Google Scholar 

  40. Hou H, Ge C, Sun H, Li H, Li J, Tian H. Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway. Cancer Sci. 2018;109:1088–100.

    Article  CAS  Google Scholar 

  41. Mygind KJ, Storiko T, Freiberg ML, Samsoe-Petersen J, Schwarz J, Andersen OM, et al. Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface. J Biol Chem. 2018;293:8077–88.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Qingqing Zhou, Tingting Huang, Zhiyuan Jiang, Chao Ge, Xiaoxia Chen, Lili Zhang, Fangyu Zhao, Miaoxin Zhu, Hong Li, Ming Yao, Jinjun Li & Hua Tian

  2. Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu Province, China

    Taoyang Chen

  3. Cancer Institute of Guangxi, Nanning, China

    Ying Cui

Authors
  1. Qingqing Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingting Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiyuan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lili Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fangyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Miaoxin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Taoyang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ying Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ming Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jinjun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hua Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hua Tian.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1131-9

This article is cited by

Search

Advanced search

Quick links