TGFBI and tumorigenesis

描述（由申请人提供）：本申请的主要目的是验证TGFBI （tgf - β诱导基因，也称为β -igh3）作为癌症诊断和预后的关键生物标志物。TGFBI是tgf - β的靶基因之一，通过基因表达谱分析发现，TGFBI在人类结直肠癌、乳腺癌和胰腺癌中存在过表达。然而，TGFBI过表达是否对肿瘤发生晚期，特别是转移有显著影响，从而作为癌症诊断和预后的信息性生物标志物，仍有待确定。在这方面，我们从异种移植模型系统中获得的初步数据强烈支持TGFBI过表达可能对肿瘤发生产生深远影响的观点。为了充分确定TGFBI过表达作为肿瘤发生的关键生物标志物，并确定TGFBI过表达促进肿瘤活性的机制，我们将重点研究三个具体目标。目的1将利用基于人类癌细胞的异种移植模型系统完成TGFBI促进转移活性的表征。目的2将利用转基因小鼠模型系统确定TGFBI对肿瘤侵袭和转移的影响。目的3将通过与特定整合素相互作用激活下游通路来确定TGFBI作用的机制。肿瘤发生是一个复杂的多步骤过程。为了通过肿瘤微环境的变化进一步了解肿瘤发生和发展的分子事件，需要识别和表征参与这一复杂病理过程的新因素。因此，这些拟议研究的完成将进一步了解TGFBI促进肿瘤发生的分子机制，并有助于开发新的人类癌症治疗方法。

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.