Cross-cellular interactions between hepatocytes and cholangiocytes: The role of NF-κB pathways in hepatocarcinogenesis

The transition from chronic injury to cancer in the liver is driven by responses of the microenvironment to distinct forms of liver cell death. Recently, we demonstrated that deletion of Traf2 and Caspase-8 in liver parenchymal cells activates canonical and non-canonical NF-κB pathways and sensitises towards necroptosis, converting hepatocytes into a sublethal state. This enabled the prolonged release of NF-κB-dependent alarmins and cytokines, thereby promoting ductular reaction, immune activation and hepatocarcinogenesis. Consequently, complete inactivation of NF-κB in hepatocytes and cholangiocytes accelerated the execution of necroptosis and converted necroptosis into a hypo-reactive cell death form, preventing initiation of hepatocarcinogenesis.

Further analysis was conducted to elucidate the specific function of canonical vs. non-canonical NF κB in mediating liver injury and liver cancer development. For this purpose, we targeted additionally IKK2 or IKK1 as central activating kinases of both NF κB pathways as well as the NF κB subunits itself via p65 or NF κB2. Our results suggest an essential function of the non-canonical NF-κB signalling pathway in cholangiocytes, since its inactivation affects not only the ductular reaction but also the development of hepatocellular carcinoma. Moreover, if necroptosis and NF-κB are only active in one of the two cell compartments, which was confirmed through hepatocyte or cholangiocyte-specific knockout lines, neither inflammation nor carcinogenesis will occur. This implies the existence of a cross-cell control mechanism between hepatocytes and cholangiocytes, depending on cell death responses during hepatocarcinogenesis.

Publication History

Article published online:
20 January 2025