Functional characterization of the chromosome 8p tumor suppressor gene interaction with tumor microenvironment in human hepatocellular carcinoma

• Applicant: Professorin Dr. Stephanie Rössler
• Subject Area: Pathology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260074059

Liver cancer is the third leading cause of cancer death worldwide and more than 85% of all liver cancer cases are hepatocellular carcinoma (HCC). The high mortality rate of HCC is mainly caused by metastasis or by de novo multifocal tumor formation in the diseased liver. In previous work using an integrative genomic and transcriptomic approach, I have shown that loss of chromosome 8p is observed in 45% of patients and is associated with poor outcome. A 10-gene 'driver' signature that predicts outcome in HCC contains six potential tumor suppressor genes (TSGs) on chromosome 8p, the bona fide TSG DLC1 and two novel TSGs, namely SORBS3 and SH2D4A. Clonogenicity assays, cell migration assays and xenograft mouse models confirmed the tumor suppressor function of SH2D4A and SORBS3. Therefore, this unbiased approach was effective in identifying a prognostic gene signature and two novel TSGs. My unpublished studies show that the gene expression profiles of patients with chromosome 8p deletion exhibit expression patterns characteristic of inhibition of interleukin-6 (IL-6) signaling. In addition, I was able to show that SH2D4A functions by repressing STAT3 signaling, whereas, SORBS3 inhibits IL-6 signaling through increase of estrogen receptor alpha (ERalpha) signaling. Thus, the first objective of this application is to elucidate the role of the recently identified TSGs SORBS3 and SH2D4A in IL-6 signaling. IL-6 signaling has been shown to be critically involved in inflammation, and especially in tumorigenesis and metastasis of HCC suggesting that SORBS3 and SH2D4A may functionally collaborate to inhibit IL-6 signaling. To this end, it will be functionally analyzed how chromosome 8p TSGs SORBS3 and SH2D4A modulate IL-6 signaling. In addition, I will investigate the effect of loss of a single versus multiple TSGs and determine the functional consequence of the loss of multiple TSGs. To elucidate the influence of SORBS3 and SH2D4A on the tumor microenvironment, an orthotopic mouse model and HCC patient samples will be studied in regard to tumor cell growth, immune cell infiltration and cytokine profiles. These findings may lead to the development of novel approaches for HCC patients with reduced SORBS3 and SH2D4A expression, thus, leading to improved HCC treatment and patient survival.

• DFG Programme: Research Grants