TGFBI and tumorigenesis

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DESCRIPTION (provided by applicant): The primary objective of this proposal is to validate TGFBI (TGF-beta-induced gene, also termed as beta-igh3) as a critical biomarker for cancer diagnosis and prognosis. As one of the target genes of TGF-beta, TGFBI has been found by gene expression profiling to be overexpressed in human colorectal cancers, as well as breast and pancreatic cancers. However, it remains to be determined if TGFBI overexpression exerts a significant effect on late stage of tumorigenesis, particularly metastasis, and consequently serves as an informative biomarker for cancer diagnosis and prognosis. In this regard, our preliminary data derived from a xenograft model system strongly support the notion that TGFBI overexpression could have a profound effect on tumorigenesis. To fully establish TGFBI overexpression as a critical biomarker in tumorigenesis and determine the mechanisms underlying the tumor-promoting activity of TGFBI overexpression, we will focus our studies on three specific aims. Aim 1 will complete the characterization of the activity of TGFBI in promoting metastasis using the human cancer cell-based xenograft model system. Aim 2 will determine the effects of TGFBI on tumor invasion and metastasis using transgenic mouse model systems. Aim 3 will determine the mechanism underlying the action of TGFBI through activation of downstream pathways by interacting with specific integrins. Tumorigenesis is a complex multistep process. To further advance our knowledge of molecular events underlying tumor initiation and progression via changes in tumor microenvironment, novel factors involved in this complex pathological process need to be identified and characterized. Thus, the accomplishment of these proposed studies will provide further understanding of the molecular mechanisms by which TGFBI promotes tumorigenesis and contribute to the development of novel therapeutics for the treatment of human cancers.