NEMO prevents hepatocarcinogenesis independently of an IKK complex function by controlling liver regeneration

The IKK complex is a central mediator of inflammatory NF-κB signaling – an important survival pathway in cancer cells. This complex consists of two catalytic subunits (IKKα and IKKβ) and a regulatory subunit (NEMO). Previous studies showed that the distinct IKK-subunits have functions beyond NF-κB signaling. The deletion of Nemo in parenchymal liver cells (NEMO^LPC-KO) induces apoptosis and compensatory proliferation leading to liver cancer. This specific phenotype does not occur by deleting the three NF-κB subunits (RelA/RelB/c-Rel). However, it is so far unknown if this presumed function of NEMO in hepatocarcinogenesis is associated with its role in controlling the I-κB-Kinase activity or if it is a completely independent function of NEMO in liver cells.

For this reason, we generated mice lacking all three IKK subunits in liver parenchymal cells (IKKα/β/NEMO^LPC-KO). The phenotype of these triple knockout animals was compared with mice lacking both catalytic subunits (IKKα/β^LPC-KO), enabling a functional dissection of the presumed I-κB-Kinase-independent function of the regulatory subunit NEMO. We show that the additional deletion of Nemo rescued IKKα/β^LPC-KO mice from lethal cholestasis and biliary ductopenia – a phenotype specifically observed in this double mutant mice. The loss of this specific IKK complex-independent function of NEMO further triggered apoptotic cell death of liver parenchymal cells (LPC) and induced a strong compensatory proliferation of the LPC compartment including cholangiocytes. In addition, the deletion of NEMO in IKKα/β^LPC-KO mice inhibited LPC necroptosis, which occurred in the double mutant mice. However, losing the expression of NEMO in this setting is not overall beneficial. We show that consistent triggering of hepatocyte death and compensatory proliferation leads again to spontaneous hepatocarcinogenesis.

Collectively, our data show that NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, and thereby cholestasis and hepatocarcinogenesis independently of an IKK-related function. Thus, NEMO and IKKα/β regulate LPC cell death and compensatory liver regeneration in functionally distinct ways. These results support the idea of different functional levels at which NEMO regulates I-κB-Kinase-independently liver inflammation and carcinogenesis.