ADAM17-induced signaling pathways in the liver are essentially involved in DNA-damage and HCC formation

Question:

Proteolytic release of ectodomains, a process termed ectodomain shedding, is an irreversible post-translational mechanism to regulate protein function and provide signals to neighbouring cells. A disintegrin and metalloprotease (ADAM) 17 is a major sheddase involved in the release of soluble growth factors like the epidermal growth factor (EGF) family and cytokines like tumour necrosis factor (TNF) α. Release of EGF family members from myeloid cells in the liver have been implicated in the control of DNA-damage and the induction of hepatocarcinogenesis. Here we addressed the question if ADAM17-induced signal pathways are involved in hepatocarcinogenesis.

Methods:

We used mice with ubiquitous or myeloid ADAM17 deficiency to analyse its role in DNA-damage repair and hepatocarcinogenesis.

Results:

We observed that activation of the EGF receptor upon DNA damage is blunted in the absence of ADAM17. Consequently, hepatocyte cell death is increased in the absence of ADAM17. We furthermore demonstrate that ADAM17-mediated induction of interleukin 6 (IL-6) trans-signaling is a major event during hepatocarcinogenesis. Ablation of IL-6 trans-signaling results in increased hepatocytic cell death upon DNA damage and a marked reduction of liver tumour formation.

Conclusion:

Interference with ADAM17 activity and the induction of IL-6 trans-signaling represents a novel therapeutical option to prevent HCC formation.