Redox mechanisms play a key role in regulating the resistance of cancer cells to programmed cell death (apoptosis) and the growth of new blood vessels from pre-existing capillary beds (angiogenesis). A redox protein critically important to both processes is thioredoxin-1 (TRX-1). Trx-1 levels are increased in many human colorectal, gastric and pancreatic cancers. We have shown that increased Trx-1 expression in colon cancer cells inhibits apoptosis and stimulates the hypoxia-induced production of the angiogenesis stimulating vascular endothelial growth factor (VEGF). Trx-1 is necessary for hypoxia induced VEFG production by permitting increased levels of the HIF-1alpha transcription factor. In silico data mining has identified several potentially important single nucleotide polymorphism (SNP) sites in the human Trx-1 gene, including one SNP in the conserved catalytic site coding sequence. The hypothesis upon which the studies are based is that the increased expression of Trx-1 in human gastrointestinal cancer inhibits apoptosis and stimulates angiogenesis leading to aggressively growing tumors with a poor clinical prognosis. Furthermore, drugs that selectively inhibit the redox activity of Trx-1 will block these processes and can be used to prevent and treat colorectal cancer. Based upon this hypothesis the specific aims of the project are: 1) To investigate the relationship between Trx-1 expression, patient survival and response to treatment in a prospective study of Dukes C and Dukes D stage colorectal cancers. 2) To investigate Trx-1 single nucleotide polymorphism?s (SNP) in normal and colorectal cancer patients. 3) To investigate mechanisms for increased angiogenesis by Trx-1 in colon cancer and 4) To investigate the mechanism of inhibitors of Trx-1 in patients with colorectal cancer. The objective of our work is to conduct basic and translational studies on the redox regulation of gastrointestinal cancer progression and chemotherapy resistance and to use this information to develop more effective ways to prevent and treat gastrointestinal cancer.
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