Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597497
4. Tumors/Liver Surgery
Georg Thieme Verlag KG Stuttgart · New York

Tumor suppressor genes SORBS3 and SH2D4A collaborate to repress IL-6/STAT3 signaling in hepatocellular carcinoma

C Ploeger
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
N Waldburger
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
A Fraas
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
B Goeppert
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
S Pusch
2   German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, Heidelberg, Germany
,
K Breuhahn
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
XW Wang
3   National Institutes of Health (NIH), Laboratory of Human Carcinogenesis, Bethesda, MD, United States
,
P Schirmacher
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
,
S Roessler
1   Heidelberg University Hospital, Institute of Pathology, Heidelberg, Germany
› Author Affiliations
Further Information
Roessler, Stephanie

Publication History

Publication Date:
19 December 2016 (online)

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    Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is the second-leading cause of cancer-related mortality worldwide. Chronic infection with hepatitis B (HBV) and C viruses (HCV) and other inflammatory liver diseases such as alcoholic and non-alcoholic steatohepatitis contribute to the development of HCC, making HCC a paradigm for inflammation and virus-induced cancer. In patients with chronic liver disease interleukin-6 (IL-6) serum levels are elevated and increase even more when HCC develops. But the regulatory mechanisms of IL-6 signaling in hepatocarcinogenesis are still poorly understood.

    Recently, we demonstrated that loss of chromosome 8 p tumor suppressor genes SH2D4A and SORBS3 is associated with poor prognosis. Furthermore, increased IL-6 signaling could be observed in patients with chromosome 8 p gene signature loss. The goal of this study was to dissect the molecular mechanisms of SORBS3 and SH2D4A mediated tumor suppression related to IL-6 signaling. We found that SORBS3 and SH2D4A function in a convergent manner to inhibit IL-6 signaling. Overexpression of SORBS3 or SH2D4A in HCC cell lines led to significant reduction of cell proliferation and colony formation. This effect was even further increased when both genes were co-expressed. SORBS3 and SH2D4A each decreased IL-6 target gene expression and reduced IL-6 induced STAT3 transcriptional activity in a luciferase reporter assay. SH2D4A physically interacts with STAT3 in in vitro co-immunoprecipitation and in situ proximity ligation assays (PLA). Thereby, SH2D4A blocks STAT3-dimerisation and leads to retention of STAT3 in the cytoplasm. SORBS3 directly binds and co-activates Estrogen Receptor alpha (ERα) leading to repression of STAT3 signaling. Furthermore, we observed binding of SH2D4A and SORBS3 to STAT1. However, STAT1 could not be activated by IL-6 in HCC cell lines. Thus, it appears that IL-6-mediated signaling is specific to STAT3 in HCC. Applying a tissue microarray (N = 127) of human HCC tissues, we found that loss of SH2D4A expression is associated with decreased infiltration of cytotoxic and regulatory T cell populations suggesting loss of tumor immune surveillance.

    Thus, loss of chromosome 8 p tumor suppressor genes SORBS3 and SH2D4A leads to increased STAT3/IL-6 signaling and decreased infiltration of cytotoxic and regulatory T cells. Therefore, SORBS3 and SH2D4A functionally cooperate to inhibit STAT3-mediated IL-6 signaling in HCC.


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    No conflict of interest has been declared by the author(s).

    Roessler, Stephanie