NF-κB functions as a tumour promoter in inflammation-associated cancer

Nature 431, 461–466 (2004)

Speaker : 吳 鳳 翎                            Place : Room 601 Commentator : 楊 倍 昌  老師                Time : 15:00-16:00

Abstract:

Two important conditions result in tumor development are carcinogen exposure and chronic inflammation. But, the mechanisms involved in chronic inflammation and tumorigenesis is still largely unknown¹. Mdr2-knockout mice developing a prototype of inflammation-associated cancer, hepatocellular carcinoma, is used to study the relationship between inflammation and cancer². Hepatocyte-specific inducible IκB-super suppressor transgenic mice were generated to monitored hepatitis and cancer progression, as activation of nuclear factor κB (NF-κB) is considered a component that links inflammation and cancer together. The distribution of TNF-α, the mediator that primarily directs NF-κBactivation, was analyzed by real-time PCR, immunostaining, and in situ messenger RNA hybridization. In order to investigate the role of NF-κB in hepatocarcinogenesis, the authorscrossed the bi-transgenic △N-IκB^hep mice with Mdr2-knockout mice to generate Mdr2^-/- △N-IkB^hep (double mutant) mice. Hepatocyte proliferation is evaluated by Bromo-deoxy uridine incorporation and Ki-67 antigen staining in both knockout and double mutant mice. It is showed that NF-κB deficiency doesn’t compromise hepatocyte proliferation. In addition, histological analysis revealed that architectural disorganization and cytological atypia are evident in 4 month-old-mice and the severity increased with age. It is found thatNF-κB inhibition doesn’t have any effect at the tumour initiation phases, only magnetic resonance imaging and histological analysis clearly discerned the knockout and Doxycycline-treated (transgene-suppressed) mice from the untreated double mutant mice. Finally, anti-TNFα antibody treatment prevented the induction of multiple anti-apoptotic genes, such as A1/Bfl1 and GADD45β regulated by NF-κB indicating TNF-α is a major driver of anti-apoptosis genes. Thus, suppression of a major signalling factor, such as NF-κB or TNFα, could be a tool to protract the premalignant phase and inhibit tumour progression in chronic inflammatory diseases with high cancer risk.

References:

1. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

2. Mauad, T. H. et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.Am.J. Pathol. 145, 1237–1245 (1994).