The impact of ADAM17 on non-cell-autonomous control of hepatic DNA damage response

The recognition and control of genomic damage is an inevitable task for every cell in living organisms. Since it impairs the cellular function, prevention of genotoxic stress is essential, especially in tissues with a high metabolic activity, such as the liver. The loss of DNA damage repair (DDR) mechanisms is linked to oncogenesis such as in breast cancer.

Protein ectodomain shedding is an irreversible post-translational modification of multiple proteins in several signal pathways. The family of "A disintegrin and metalloproteases" (ADAM) and ADAM17 in particular are key enzymes of that processing mode. ADAM17 is a major regulator of Interleukin 6 (IL-6) signaling which, in turn, is involved in tumorigenesis of hepatocellular carcinomas (HCC).

In the present study, we used mouse lines with ubiquitous or myeloid-specific genetic ADAM17 deficiency and induced DNA double strand breaks in the liver by injection of diethylnitrosamine. Our results show that ADAM17 regulates the liberation of EGFR ligands in a cell type-specific manner by inhibiting ligand expression and that the strength of this effect differs between hepatocytes and myeloid cells. Moreover, we show an ADAM17-dependent inhibition of IL-6-mediated STAT3 activation and, surprisingly, a compensatory release of sIL-6R despite ADAM17 deficiency. Furthermore, we demonstrate that upon DNA damage, ADAM17 regulates hepatocellular apoptosis and myeloid cell infiltration into the liver. Our results suggest that those processes are mediated by the interaction between hepatocytes and Kupffer cells.


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