The role of NAG-1 in Tumorigenesis

This dissertation explores the nature of a divergent member of the Transforming Growth Factor-β [beta] superfamily, the non-steroidal anti-inflammatory drugs activated gene (NAG-1), as it relates to its regulation and biological activity in cancer context. Our lab has extensively studied on the molecular mechanism by which phytochemicals and NSAIDs induce apoptosis correlation with NAG-1 expression in human colorectal cancer (CRC) cells. Significant data from in vitro studies suggest that NAG-1 has an anti-tumorigenic activity which elicits apoptosis in a cyclooxygenase (COX)-independent manner in CRC cells. Indeed, NAG-1 transgenic mice developed less aberrant polyp foci (APC) compared to those of control counterpart in chemically- , genetically induced colorectal cancer models. However, it has been reported that NAG-1 has a tumor-promoting activity in a different cancer type such as prostate cancer and in chapter 1, a literature review for the regulation and the role of NAG-1 in the context of cancer will be discussed. Human pancreatic cancer cells treated with the PPARγ [gamma] ligand MCC-555 showed the feature of apoptosis with associated with NAG-1 induction. MCC-555 induces KLF4 expression via PPARγ-independent pathway, which in turn induces NAG-1 transactivation by which KLF4 binds to NAG-1 promoter region, suggesting NAG-1 is also implicated in apoptosis in human pancreatic cancer cells (Chapter 2). During the study on the signaling pathway and target genes affected by NAG-1, we observed nuclear expression of NAG-1. Nuclear NAG-1 moderates TGFβ signaling by interfering binding of Smad complex to DNA, leading to the inhibition of cell migration and invasion induced by TGFβ signaling (Chapter 3). Taken together, the studies presented in this dissertation suggest that NAG-1 maybe a driver factor for apoptosis not only in CRC cells, but in pancreatic cancer cells, and this effect might arise from the activity of nuclear NAG-1 which attenuates Smad signaling required for cancer survival and progression.