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

Abstract

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.

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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.

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Funding

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

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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.

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The authors declare no competing interests.

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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.

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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). https://doi.org/10.1038/s41374-022-00727-5

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