Suppressors of Cytokine Signaling and Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a common malignancy worldwide. The HCC generally develops in the liver of patients already suffering from chronic liver disease. There have been significant advances in both the curative and palliative treatment of HCC. Although liver resection is a curative treatment for HCC, its indication is often limited due to an impaired liver function reservoir. There is still a need to understand how to control liver regeneration after resection and find better cancer immunotherapy and anticancer drugs for advanced HCC. Suppressors of cytokine signaling (SOCS) negatively regulate cytokine signaling related to cell proliferation, differentiation, and immune response; therefore, SOCS are thought to play an important role in HCC development and liver regeneration. ABSTRACT: Cytokines are secreted soluble glycoproteins that regulate cellular growth, proliferation, and differentiation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling and form a classical negative feedback loop in the signaling pathways. There are eight members of the SOCS family. The SOCS proteins are all comprised of a loosely conserved N-terminal domain, a central Src homology 2 (SH2) domain, and a highly conserved SOCS box at the C-terminus. The role of SOCS proteins has been implicated in the regulation of cytokines and growth factors in liver diseases. The SOCS1 and SOCS3 proteins are involved in immune response and inhibit protective interferon signaling in viral hepatitis. A decreased expression of SOCS3 is associated with advanced stage and poor prognosis of patients with hepatocellular carcinoma (HCC). DNA methylations of SOCS1 and SOCS3 are found in HCC. Precise regulation of liver regeneration is influenced by stimulatory and inhibitory factors after partial hepatectomy (PH), in particular, SOCS2 and SOCS3 are induced at an early time point after PH. Evidence supporting the important role of SOCS signaling during liver regeneration also supports a role of SOCS signaling in HCC. Immuno-oncology drugs are now the first-line therapy for advanced HCC. The SOCS can be potential targets for HCC in terms of cell proliferation, cell differentiation, and immune response. In this literature review, we summarize recent findings of the SOCS family proteins related to HCC and liver diseases.