Funktionelle Charakterisierung der Chromosom 8p Tumorsuppressorgen Interaktion mit der Tumormikroumgebung im menschlichen hepatozellulären Karzinom
Zusammenfassung der Projektergebnisse
The high mortality rate of HCC is mainly caused by metastasis or de novo multifocal tumor formation in the diseased liver. Genomic alterations are a hallmark of tumor formation in most solid tumor types. In HCC, high heterogeneity in terms of number of genomic alterations per tumor and of regions affected by genomic alterations has been observed. In previous work using an integrative genomic and transcriptomic approach, we showed that in HCC loss of chromosome 8p is observed in 45% of tumors and is associated with poor patient outcome. Interestingly, chromosome 8p deletion has also been observed in about 50% of breast, lung and colon carcinomas and the involved deletions mostly involve the whole chromosome 8p arm. In addition, we identified SORBS3 and SH2D4A as two novel tumor suppressor genes on chromosome 8p and showed that the gene expression profiles of patients with chromosome 8p deletion exhibit expression patterns characteristic of inhibition of interleukin-6 (IL-6) signaling. It has been shown that IL-6 signaling is a key activated pathway in inflammation, and is especially involved in development and metastasis of HCC. In this project, we were able to demonstrate that SH2D4A and SORBS3 functionally collaborate to inhibit HCC cell growth. Both proteins, SH2D4A and SORBS3, inhibit IL-6 mediated STAT3 signaling and SH2D4A and SORBS3 directly bind to STAT3 in vitro and in situ. In human HCC tumor tissues SH2D4A expression correlates with infiltration of FOXP3-positive T cells but not B cells or macrophages. In addition, we showed that SH2D4A and SORBS3 directly interact with STAT1 protein and high expression of SH2D4A or SORBS3 leads to enhanced IFNγ/STAT1 signaling. These findings are consistent with a tumor suppressive function of STAT1 which has been reported before in multiple tumor entities. Thus, the chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3- mediated IL-6 signaling in HCC cells.
Projektbezogene Publikationen (Auswahl)
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(2018) Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology (Baltimore, Md.) 67 (5) 1842–1856
Wan, Shan; Meyer, Anne-Sophie; Weiler, Sofia Maria Elisabeth; Rupp, Christian; Tóth, Marcell; Sticht, Carsten; Singer, Stephan; Thomann, Stefan; Roessler, Stephanie; Schorpp-Kistner, Marina; Schmitt, Jennifer; Gretz, Norbert; Angel, Peter; Tschaharganeh,
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(2016) Cellular apoptosis susceptibility (CAS) is linked to integrin β1 and required for tumor cell migration and invasion in hepatocellular carcinoma (HCC). Oncotarget 7(16):22883-92
Winkler J, Roessler S, Sticht C, DiGuilio AL, Drucker E, Holzer K, Eiteneuer E, Herpel E, Breuhahn K, Gretz N, Schirmacher P, Ori A, Singer S
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(2016) Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology 64(3):828-42
Ploeger C, Waldburger N, Fraas A, Goeppert B, Pusch S, Breuhahn K, Wang XW, Schirmacher P, Roessler S
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(2017) Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. J Hepatol 66(5):919-929
Farquhar MJ, Humphreys IS, Rudge SA, Wilson GK, Bhattacharya B, Ciaccia M, Hu K, Zhang Q, Mailly L, Reynolds GM, Ashcroft M, Balfe P, Baumert TF, Roessler S, Wakelam MJO, McKeating JA
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(2017) Proteomic Analysis Reveals GMP Synthetase as p53 Repression Target in Liver Cancer. Am J Pathol 187(2):228-235
Holzer K, Drucker E, Roessler S, Dauch D, Heinzmann F, Waldburger N, Eiteneuer EM, Herpel E, Breuhahn K, Zender L, Schirmacher P, Ori A, Singer S
