Linking chronic inflammation with tumor suppressor gene inactivation in liver cancer

• Applicant: Professorin Dr. Stephanie Rössler
• Subject Area: Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493697503

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 associated with poor patient outcome. In addition, we identified SORBS3 and SH2D4A as two novel tumor suppressor genes on chromosome 8p, which are associated with expression patterns characteristic of reduced interleukin-6 (IL-6) signaling. IL-6 signaling is critically involved in inflammation, and especially in tumorigenesis and metastasis of HCC suggesting that SORBS3 and SH2D4A may modulate the immune cell induced IL-6/STAT3 signaling in liver cancer cells. Recently, we demonstrated that SH2D4A and SORBS3 functionally cooperate to inhibit IL-6/STAT3 signaling and HCC cell growth. In addition, we demonstrated that SH2D4A directly interacts with the mitochondrial protein prohibitin 1 (PHB1) and SH2D4A knockdown alters basal mitochondrial respiration and mitochondrial ATP production. The usage of the selective PHB inhibitor FL3 led to a repression of these effects suggesting that SH2D4A may be involved in mitochondrial function and inhibition by FL3 may rescue the effects of SH2D4A loss in tumor cells. Thus, we were able to functionally characterize and molecularly dissect the role of the chromosome 8p tumor suppressor gene SH2D4A. In the next stage of the project, we aim to broaden the project by identification of genes essential in chromosome 8p deleted HCCs which are associated with tumor progression and response to the tumor microenvironment. To this end, we have identified FOXM1 to be essential in HCC cells with wildtype chromosome 8p, whereas PARD3/PARD6B were essential in HCC cells with chromosome 8p deletion. In the here proposed project, we aim to dissect essential genes in HCC with or without chromosome 8p deletion in regard to inflammatory IL-6 signaling. Thus, we will functionally dissect the role of FOXM1 (Aim 1) and of PARD3/PARD6B (Aim 2) in HCCs with or without chromosome 8p deletion. Furthermore, we will identify chromosome 8p associated essential genes using our engineered chromosome 8p deleted and corresponding wildtype cells with or without IL-6 exposure (Aim 3) and functionally dissect candidate genes essential in HCC with chromosome 8p deletion and STAT3 activation.

• DFG Programme: Research Grants