Skip to main content

Volume 2 Supplement 3

Abstracts of the 29th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)

  • Poster presentation
  • Open access
  • Published:

IKKα modulates primary sclerosing cholangitis and intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer after hepatocellular carcinoma (HCC). The risk of ICC is higher in patients with primary sclerosing cholangitis (PSC). To date, the cellular and molecular mechanism underlying the pathological progression of PSC and ICC is poorly understood. IKKα is part of the IκB kinase (IKK) complex, which plays an important role in regulating inflammation- associated carcinogenesis through both NF-κB-dependent and independent pathways. Here, we show that IKKα mutant mice developed very serious PSC as early as four weeks of age. The ALT/AST and bilirubin levels were significantly increased in the serum of IKKα mutant mice along with lymphocytic and eosinophilic infiltration into the liver. Liver inflammation in the IKKα mutant mice, mediated by macrophages, neutrophils and CD4 T cells, was associated with the death of cholangiocytes and hepatocytes, and obstruction of intrahepatic and extrahepatic bile ducts, which impeded bile flow and ultimately led to biliary fibrosis and cirrhosis. Additionally, upon activation of NOTCH signaling in the liver via hydrodynamic shear, we observed that NOTCH-induced ICC, with the PSC, developed significantly faster in IKKα mutant mice. To identify whether intrinsic IKKα dysfunction in hepatocytes promotes the NOTCH-induced ICC in IKKα mutant mice, we generated IKKα hep KO mice, in which IKKα is conditionally knocked out in hepatocytes. No biliary disease or liver injury was observed in these mice. We then established an accelerated ICC model utilizing hydrodynamic delivery of NICD and AKT expression vectors. Unexpectedly, ICC development was remarkably slower in the IKKα hep KO mice compared to the IKKα floxed control mice, and this delayed ICC development was associated with reduced activation or levels of AKT, NOTCH, MAPK/Erk and c-myc. These data suggest that IKKα may play a protective role in PSC, while promoting ICC derived from hepatocytes. In contrast to ICC, we also established the cMET/β-catenin-induced HCC model in the IKKα hep KO mice, which did not reveal any difference in tumor development between IKKα hep KO and control mice. Taken together, our findings suggest that IKKα plays complicated and important roles in PSC and ICC pathological progression.

Author information

Authors and Affiliations


Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Q., Scarzello, A.J., Xiao, Z. et al. IKKα modulates primary sclerosing cholangitis and intrahepatic cholangiocarcinoma. j. immunotherapy cancer 2 (Suppl 3), P171 (2014).

Download citation

  • Published:

  • DOI: