Non-canonical NF-κB signaling induces proliferation in primary liver cancer

Background and Aims Primary liver cancer is the third leading cause of cancer related death with increasing incidence and mortality worldwide. Recent studies demonstrate a role of non-canonical nuclear factor kappa B (NF-κB) signaling in various chronic liver diseases. Here, we aimed to further elucidate the role of non-canonical NF-κB signaling and its key transcription factor RELB in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA).

Methods Non-canonical NF-κB signaling was manipulated in human HCC and iCCA cell lines by treatment with recombinant human Lymphotoxin α1/β2 ([LTα1/β2] pathway inducer). Subsequently, protein expression, cell death and proliferation were determined by Western blot analysis, flow cytometry and continuous impedance measurement, respectively. Murine HCC and intrahepatic CCA (iCCA) models were generated by hydrodynamic tail vein injection of plasmids carrying cMET/β-Catenin (HCC) or AKT/NOTCH1 (iCCA). Non-canonical NF-κB signaling in murine liver tissue was assessed by immunohistochemistry and qRT-PCR.

Results In both murine models a significant upregulation of RELB has been observed in tumor cells. Furthermore, Lymphotoxin-β has been identified, among other possible ligands, as being the prevailing pathway inducer. In line thereto, LTα1/β2 treatment led to enhanced RELB expression and its nuclear translocation in vitro and induced proliferation of all HCC cell lines and one iCCA cell line that showed low basal RELB expression.

Conclusion Lymphotoxin-β as the predominant ligand induces non-canonical NF-κB signaling in primary liver tumors, leading to a significant induction of tumor cell proliferation.

Publication History

Article published online:
26 January 2022