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B01: Linking chronic inflammation with tumor suppressor gene inactivation in liver cancer

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. Taken together these findings suggest that SORBS3 and SH2D4A may modulate IL-6 signaling. Recently, we were able to demonstrate that SH2D4A and SORBS3 functionally collaborate to inhibit IL-6 mediated STAT3 signaling and HCC cell growth. However, the molecular mechanisms of modulation of STAT3 signaling by SH2D4A and SORBS3 are still unclear. In addition, 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 had been reported in multiple tumor entities. Thus, the objective of this application is to elucidate the role of chromosome 8p tumor suppressor genes in IL-6/STAT3 signaling. To this end, we will 1) functionally dissect how SORBS3 and SH2D4A modulate IL-6/STAT3 signaling and the cross-talk of STAT3 and STAT1 at the molecular level, 2) investigate the loss of chromosome 8p regions, harboring SORBS3 and SH2D4A, engineered by CRISPR/Cas9 in immortalized hepatocytes and 3) determine the influence of SORBS3 and SH2D4A on the tumor microenvironment, immune cell infiltration, and cytokine profiles in a murine orthotopic HCC model, in human HCC tissues,and co-culture experiments.




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