Colorectal cancer (CRC) often develops from hyperplasia associated with inflammatory bowel disease (IBD). IBD is a frequent chronic inflammatory disorder affecting 2,2 million people in Europe. IBD is represented mainly by two diseases, the ulcerative colitis and Crohn´s disease. 15% of IBD patients die from colorectal cancer (colitis-associated cancer, CAC). While the etiology of IBD is still unknown aberrant inflammatory responses in the intestinal tissues are clearly involved in the onset and progression of the disease.
Animal models revealed that inappropriate immune responses of intestinal macrophages, T cells or the intestinal epithelium as well as disturbances in the composition of the intestinal microflora may cause the disease. Thus, therapies that aim at the restoration of balanced immune environment in the affected intestinal tissues are regarded as the most promising clinical strategies.
The mRNA-binding proteins HuR and TTP are known to regulate mRNA turnover of several genes that play a fundamental role in IBD and CAC. Consequently, both HuR and TTP are able to profoundly change the expression levels of several genes critically involved in IBD and CAC. TTP is generally regarded as an mRNA-destabilizing factor, whereas HuR is a protein with a predominantly mRNA-stabilizing function.
Biological activity of TTP is regulated by its expression rate, protein stability and phosphorylation whereas that of HuR is regulated predominantly by phosphorylation and subcellular localization. TTP is a key factor in immune homeostasis which is best documented by the phenotype of the TTP-deficient mice. These animals develop various inflammatory and autoimmune syndromes (e.g. arthritis, cachexia, dermatitis) approximately 2 months thus preventing the analysis of TTP function in disease models. Conditional deletion of HuR in the T cell compartment indicated HuR to be required for normal T cell pool generation. The importance of HuR for immune responses has been confirmed also in a transgenic HuR overexpression mouse that displayed inhibition of translation of several inflammatory mediators. Consistent with its positive effect on mRNA stability HuR is overexpressed in several tumors thus allowing increased expression of pro-inflammatory and survival factors.
In contrast, TTP is a strong anti-inflammatory factor with a reported tumor-suppressor activity as inhibitor of cell growth and tumor vascularization. In addition, HuR and TTP expression levels appear to be regulated in a strictly opposite way in the intestinal mucosa as indicated in a recent analysis of colon cancer tissues: high TTP and low HuR in healthy tissues, low TTP and high HuR in tumor tissues. However, to date no study has been published addressing the functional role of HuR or TTP in inflammatory or malignant diseases, or the suitability of these proteins as therapeutic targets. We have chosen IBD and CAC to investigate the role of HuR and TTP in the onset and progression of these disorders, as well as to provide a proof-of-principle for the therapeutic potential of these mRNA decay-regulating proteins and their modulation by low molecular weight compounds.
The project will capitalize on the availability of TTPfl/fl animals generated recently in our lab and on the use of the first pharmacological inhibitors of HuR that were shown to block production of inflammatory cytokines.