TGF-β1 is an anti-inflammatory cytokine recognised as a key regulator of immunological homeostasis and inflammatory responses. Furthermore, TGF-β1 is important for the regulation of cell growth, differentiation and apoptosis in a wide range of tissues including the intestinal epithelium. Reduced TGF-β1 activity is thought to be responsible for the development of autoimmune disorders in several pathological conditions, including inflammatory bowel disease [IBD]. Although the cause of IBD is not yet known, research has shown that a number of factors may be involved including environment, diet and genetics, as well as cytokine exposure. Importantly, IBD is also associated with an increased lifetime risk of developing colorectal cancer, which remains the fourth most common cancer worldwide, representing a significant therapeutic challenge. As functionally implicated in both maintenance of the immune response and tissue homeostasis in the colon, TGF-β1 signalling potentially sits at the crossroads between aberrant inflammation and colorectal tumorigenesis. Hence, the purpose of this paper is to review the evidence for cross talk between TGF-β1 signalling and pathways important for colorectal tissue homeostasis, with the emphasis on understanding how deregulation of TGF-β1 signalling contributes not only to aberrant inflammatory disease but also to colorectal tumour progression.

Understanding the mechanisms that promote aberrant tumour cell survival is critical for the determination of novel strategies to combat colorectal cancer. We have recently shown that the anti-apoptotic protein BAG-1, highly expressed in pre-malignant and colorectal cancer tissue, can potentiate cell survival through regulating NF-κB transcriptional activity. In this study, we identify a novel complex between BAG-1 and the p50-p50 NF-κB homodimers, implicating BAG-1 as a co-regulator of an atypical NF-κB pathway. Importantly, the BAG-1-p50 complex was detected at gene regulatory sequences including the epidermal growth factor receptor [EGFR] and COX-2 [PTGS2] genes. Suppression of BAG-1 expression using siRNA was shown to increase EGFR and suppress COX-2 expression in colorectal cancer cells. Furthermore, mouse embryonic fibroblasts derived from the NF-κB1 [p105/p50] knockout mouse were used to demonstrate that p50 expression was required for BAG-1 to suppress EGFR expression. This was shown to be functionally relevant as attenuation of BAG-1 expression increased ligand activated phosphorylation of EGFR in colorectal cancer cells. In summary, this paper identifies a novel role for BAG-1 in modulating gene expression through interaction with the p50-p50 NF-κB complexes. Data presented led us to propose that BAG-1 can act as a selective regulator of p50-p50 NF-κB responsive genes in colorectal tumour cells, potentially important for the promotion of cell survival in the context of the fluctuating tumour microenvironment. As BAG-1 expression is increased in the developing adenoma through to metastatic lesions, understanding the function of the BAG-1-p50 NF-κB complexes may aid in identifying strategies for both the prevention and treatment of colorectal cancer.

As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor beta [TGF-β1] expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by siRNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and ChIP assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1 dependent NRK fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1 sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis.

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