Skip to main content

Thank you for visiting 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.

The E3 ubiquitin ligase SOCS-7 reverses immunosuppression via Shc1 signaling in hepatocellular carcinoma


Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies and is the third leading cause of tumor-related mortality worldwide. Despite advances in HCC treatment, diagnosis at the later stages, and the complex mechanisms relating to the cause and pathogenesis, results in less than 40% of HCC patients being eligible for potential therapy. Prolonged inflammation and resulting immunosuppression are major hallmarks of HCC; however, the mechanisms responsible for these processes have not been clearly elucidated. In this study, we identified SOCS-7, an inhibitor of cytokine signaling, as a novel regulator of immunosuppression in HCC. We found that SOCS-7 mediated E3 ubiquitin ligase activity on a signaling adaptor molecule, Shc1, in Huh-7 cells. Overexpression of SOCS-7 reduced the induction of immunosuppressive factors, TGF-β, Versican, and Arginase-1, and further reduced STAT3 activation. Furthermore, using an in vivo tumor model, we confirmed that SOCS-7 negatively regulates immunosuppression and inhibits tumor growth by targeting Shc1 degradation. Together, our study identified SOCS-7 as a possible therapeutic target to reverse immunosuppression in HCC.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: SOCS-7 expression is downregulated in hepatocellular carcinoma (HCC).
Fig. 2: Upregulated SOCS-7 inhibits hepatocellular carcinoma (HCC) growth in vitro.
Fig. 3: Overexpression of SOCS-7 inhibits the growth of HCC in vivo.
Fig. 4: SOCS-7 degrades Shc1 by ubiquitination.
Fig. 5: SOCS-7 mediated downregulation of immunosuppressive factors via Shc1.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


  1. WHO. International Agency for Research on Cancer. Liver. (2018).

  2. Golabi, P. et al. Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities. Medicine (Baltimore). 96, e5904 (2017).

    Article  Google Scholar 

  3. Levrero, M. & Zucman-Rossi, J. Mechanisms of HBV-induced hepatocellular carcinoma. J. Hepatol. 64, S84–S101 (2016).

    CAS  Article  Google Scholar 

  4. Balogh, J. et al. Hepatocellular carcinoma: a review. J. Hepatocell Carcinoma. 3, 41–53 (2016).

    Article  Google Scholar 

  5. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 389, 2492–2502 (2017).

    CAS  Article  Google Scholar 

  6. Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).

    Article  Google Scholar 

  7. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature. 387, 917–921 (1997).

    CAS  Article  Google Scholar 

  8. Ilangumaran, S., Ramanathan, S. & Rottapel, R. Regulation of the immune system by SOCS family adaptor proteins. Semin Immunol. 16, 351–365 (2004).

    CAS  Article  Google Scholar 

  9. Hilton, D. J. et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci USA. 95, 114–119 (1998).

    CAS  Article  Google Scholar 

  10. Huang, Y. et al. Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology 132, 733–744 (2007).

    CAS  Article  Google Scholar 

  11. Yang, R. et al. p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO. Sci. Rep. 7, 43409 (2017).

    Article  Google Scholar 

  12. Martens, N. et al. Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation. J. Biol. Chem. 280, 13817–13823 (2005).

    CAS  Article  Google Scholar 

  13. Fu, B. et al. PTPN14 aggravates inflammation through promoting proteasomal degradation of SOCS7 in acute liver failure. Cell Death Dis. 11, 803 (2020).

    CAS  Article  Google Scholar 

  14. Sasi, W., Ye, L., Jiang, W. G., Sharma, A. K. & Mokbel, K. In vitro and in vivo effects of suppressor of cytokine signalling 7 knockdown in breast cancer: the influence on cellular response to hepatocyte growth factor. Biomed Res. Int. 2014, 648040 (2014).

    Article  Google Scholar 

  15. Onnis, A. et al. The pro-oxidant adaptor p66SHC promotes B cell mitophagy by disrupting mitochondrial integrity and recruiting LC3-II. Autophagy. 14, 2117–2138 (2018).

    CAS  Article  Google Scholar 

  16. Wright, K. D. et al. The p52 isoform of SHC1 is a key driver of breast cancer initiation. Breast Cancer Res. 21, 74 (2019).

    Article  Google Scholar 

  17. Ahn, R. et al. The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression. Nat Commun. 8, 14638 (2017).

    Article  Google Scholar 

  18. Moreira, D. et al. STAT3 inhibition combined with CpG immunostimulation activates antitumor immunity to eradicate genetically distinct castration-resistant prostate cancers. Clin. Cancer Res. 24, 5948–5962 (2018).

    CAS  Article  Google Scholar 

  19. Huang, P. et al. p66Shc promotes HCC progression in the tumor microenvironment via STAT3 signaling. Exp. Cell Res. 383, 111550 (2019).

    CAS  Article  Google Scholar 

  20. Guo, R. et al. MET IHC is a poor screen for MET amplification or MET Exon 14 mutations in lung adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium. J. Thorac. Oncol. 14, 1666–1671 (2019).

    CAS  Article  Google Scholar 

  21. Paschalis, A. et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur. Urol. 76, 469–478 (2019).

    CAS  Article  Google Scholar 

  22. Krebs, D. L. & Hilton, D. J. A new role for SOCS in insulin action. Suppressor of cytokine signaling. Sci. STKE. 2003, PE6 (2003).

    Article  Google Scholar 

  23. Li, Y. et al. An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network. Nat. Commun. 8, 347 (2017).

    Article  Google Scholar 

  24. Piessevaux, J. et al. Functional cross-modulation between SOCS proteins can stimulate cytokine signaling. J. Biol. Chem. 281, 32953–32966 (2006).

    CAS  Article  Google Scholar 

  25. Yoshikawa, H. et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat. Genet. 28, 29–35 (2001).

    CAS  PubMed  Google Scholar 

  26. Niwa, Y. et al. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24, 6406–6417 (2005).

    CAS  Article  Google Scholar 

  27. Weber-Nordt, R. M. et al. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood 88, 809–816 (1996).

    CAS  Article  Google Scholar 

  28. Danial, N. N., Pernis, A. & Rothman, P. B. Jak-STAT signaling induced by the v-abl oncogene. Science 269, 1875–1877 (1995).

    CAS  Article  Google Scholar 

  29. Lu, C. et al. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer 18, 130 (2019).

    Article  Google Scholar 

  30. Chen, J. et al. Analysis of genomes and transcriptomes of hepatocellular carcinomas identifies mutations and gene expression changes in the transforming growth factor-beta pathway. Gastroenterology 154, 195–210 (2018).

    CAS  Article  Google Scholar 

  31. Tanaka, Y. et al. Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression. Oncogenesis 5, e277 (2016).

    CAS  Article  Google Scholar 

  32. Zhangyuan, G. et al. VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway. Oncogene 39, 1213–1230 (2020).

    CAS  Article  Google Scholar 

  33. Kershaw, N. J., Murphy, J. M., Lucet, I. S., Nicola, N. A. & Babon, J. J. Regulation of Janus kinases by SOCS proteins. Biochem. Soc. Trans. 41, 1042–1047 (2013).

    CAS  Article  Google Scholar 

  34. Matsuda, S., Saito, H. & Nishiyama, N. Basic fibroblast growth factor suppressed the enhancement of choline acetyltransferase activity induced by nerve growth factor. Neurosci. Lett. 114, 69–74 (1990).

    CAS  Article  Google Scholar 

  35. Yu, S. et al. Autophagy in the “inflammation-carcinogenesis” pathway of liver and HCC immunotherapy. Cancer Lett. 411, 82–89 (2017).

    CAS  Article  Google Scholar 

Download references


The research is supported by National Natural Science Foundation of China (NSFC), No. 81772590, 81972233.

Author information

Authors and Affiliations



P.H. participated in the design of the study, animal model construction and the tissue collection, cultured cells and drafted the manuscript. Z.Z. and Y.C. participated in cultured cells and performed the data analysis. B.Y. assisted with the animal model construction and drafted the manuscript. J.X. conceived and participated in the design of the study, and final approval of the version to be submitted. All authors read and approved the final paper.

Corresponding author

Correspondence to Jinglin Xia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal experimentation was approved by Institutional Animal Care and Use Committee of the Fudan University, Shanghai, China. All experiments were conducted according to guidelines approved by the Zhongshan Hospital affiliated with Fudan University.

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

Verify currency and authenticity via CrossMark

Cite this article

Huang, P., Zhao, Z., Chen, Y. et al. The E3 ubiquitin ligase SOCS-7 reverses immunosuppression via Shc1 signaling in hepatocellular carcinoma. Lab Invest 102, 613–620 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links