INFLAIDCAN · The role of activation-induced cytidine deaminase in inflammation-induced carcinogenesis
FP7 — People (Marie Curie Actions)
- Duration
- 2010-03-01 → 2011-08-31
- EU contribution
- €161,900
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
The role of activation-induced cytidine deaminase in inflammation-induced carcinogenesis
Cancer development implies the sequential accumulation of pro-neoplasic events in DNA. The DNA-modifying enzyme activation-induced cytidine deaminase (AID) was shown to contribute to the generation of malignancies in B cells by promoting chromosome translocations and mutations. Recently, expression of AID has also been reported in non-B cells upon stimulation with different inflammatory cytokines. Furthermore, AID expression was detected in different types of carcinomas and correlated with the presence of mutations in proto-oncogenes. These data suggest a link between inflammation, AID expression and cancer development. The objective of the present research project was to examine a potential role of AID in inflammation-induced carcinogenesis in vivo. We therefore aimed at establishing an experimental setup based on the previously described colitis-induced cancer model that would allow us to compare tumour incidence, size and aggressiveness between wild type and AID-/- animals. Our data show that colon carcinoma cells up-regulate the expression of AID upon stimulation with the inflammatory cytokine TNF-α in vitro. Furthermore, experiments using a modification of the colitis-induced cancer model showed a significant reduction in the incidence of aggressive adenocarcinomas in AID-/- mice as compared to wt animals. These data show for the first time that in the context of chronic inflammation AID contributes to the neoplastic transformation of non-B cells and significantly add to our understanding of the mechanisms that underlie the generation of potentially oncogenic mutations and cancer development. Further experiments to confirm these results in wild type and the tumour-prone MSH2-/- background are currently ongoing. To quantitatively assess AID activity, we generated a reporter system that is based on the AID-mediated activation of the oncogenic V12 mutant of KRas. Data from in vitro experiments show that AID activity is indeed necessary and sufficient to induce the expression KRasV12 in this system. The generation of knock-in mice expressing this reporter system in colon epithelial cells is currently underway. In summary, the work performed in the course of the present project shows that the inflammatory cytokines induce the expression of AID in colon epithelial cells. Moreover, our data indicate that AID plays a role in the development of aggressive colon adenocarcinomas in response to chronic inflammation in mice. Together, these data strongly suggest that in the context of chronic inflammation the mutagenic activity of AID contributes to the neoplastic transformation of epithelial cells. Thus, although several questions remain open, the project has added substantial knowledge to the understanding of cancer development.
Data: CORDIS, © European Union
Project objective
Activation-induced cytidine deaminase (AID) is a DNA-modifying enzyme essential for somatic hypermutation and class switch recombination in B cells. However, deregulation of AID can induce mutations and chromosomal translocations in B cells thus promoting neoplastic transformation and cancer development. AID expression is controlled by several transcription factors like those of the Rel/NF-kappa B family. The NF-kappa B pathway can be activated by a variety of different stimuli and constitutive activation of NF-kappa B is implicated in various malignancies. Indeed, the well established link between chronic inflammation and cancer has been correlated to constitutive NF-kappa B activation by inflammatory cytokines. Although the expression of AID was originally thought to be restricted to B cells, it has been shown recently that stimulation with inflammatory cytokines also induces AID expression in different epithelial cells. Furthermore, expression of AID has been found in hepatocarcinomas, gastric cancer and bile duct carcinomas suggesting a link between inflammation, NF-kappaB activation, AID expression and cancer development. However, it remains unclear if in the observed cases AID expression is just a by-product of NF-kappa B activity or if AID actively contributes to cancer development and/or progression in vivo. In the proposed research project, I am aiming to address the role of AID in the development and progression of carcinomas in vivo. For this purpose, I am going to compare the tumour incidence and aggressiveness between wt and AID-/- mice in a model for colitis-induced carcinogenesis. In addition, I am planning to generate a reporter system in which the expression of the oncogenic KRasV12 mutant depends on the reversion of a STOP codon by AID. This will decrease the amount of mutations required for tumour development and will allow for the efficient tracking and quantification of AID activity in different tissues in vitro and in vivo.
Original text from CORDIS.
Participants
- FUNDACION SECTOR PUBLICO ESTATAL CENTRO NACIONAL INVESTIGACIONES ONCOLOGICAS CARLOS III · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union