Basis for the role of NF-kB in Inflammation & Cancer

Abstract

The 19th-century pathologist Virchow noted an association between inflammation and cancer. This initial observation has been supported by recent epidemiological data, which has lead to the estimation that 20% of cancers are linked to chronic infections and persistent inflammation. Primary examples are gastric cancer, hepatocellular carcinoma (HCC), viral hepatitis and colitis- associated cancer. The NF-κB signalling pathway has particular relevance for several liver diseases including hepatitis, liver fibrosis and hepatocellular carcinoma. Constitutive NF-κB activation is a hallmark for many cancers and a major link between inflammation and cancer is provided by NF-κB transcription factor. Inhibition of apoptosis is perhaps the most obvious way through which NF-κB signalling promotes the development of cancer. Numerous NF-κB target genes, such as Gadd45β, prevent apoptosis and have been shown to be required for liver regeneration post-partial hepatectomy. The precise mechanism by which NF-κB regulates the inflammatory mechanisms that drive tumourigenesis, however are poorly understood. In order to elucidate these mechanisms, we propose to examine the role of Gadd45β in the NF-κB mediated link between inflammation and cancer. This study reports that Gadd45β deficient mice are more resistant to diethylnitrosamine (DEN) induced hepatocellular carcinogenesis. Gadd45β knockout (KO) mice developed HCC approximately four-fold lower than in control mice. Tumour number and maximum tumour size were also markedly reduced in KO mice. To further investigate in which cell types Gadd45β exerts its tumourigenic action we used bone marrow chimeric mice. Results have demonstrated that Gadd45β exerts its tumourigenic action primarily within the bone marrow derived cells but not in hepatocytes specifically during tumour progression stage than in tumour initiation stage. Furthermore, bone marrow-derived macrophages from KO mice preferentially polarised more towards macrophage M1 like phenotype that promotes anti-tumour immunity and inflammation.

Thus, here we report a previously unidentified mechanism by which NF-κB linked inflammation to cancer and identified Gadd45β as a putative mediator of the NF-κB’s tumourigenic activity.