TGFBI and tumorigenesis

TGFBI 与肿瘤发生

• 批准号: 7135191
• 负责人: XIAO-FAN WANG
• 金额: $ 29.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135191
• 关键词: biomarker; colorectal neoplasms; gene expression profiling; gene targeting; genes; genetically modified animals; human; integrins; mammary gland; metastasis; model; neoplasm /cancer; neoplasm /cancer diagnosis; neoplastic cell; pancreas neoplasms; prognosis; xenotransplantation

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.

描述（由申请人提供）：本提案的主要目的是验证TGFBI（TGF-β诱导基因，也称为β-igh 3）作为癌症诊断和预后的关键生物标志物。 作为TGF-β的靶基因之一，已通过基因表达谱发现TGFBI在人类结直肠癌以及乳腺癌和胰腺癌中过表达。 然而，TGFBI过表达是否对肿瘤发生的晚期，特别是转移发挥显著作用，并因此作为癌症诊断和预后的信息生物标志物，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。 为了充分确立TGFBI过表达作为肿瘤发生中的关键生物标志物，并确定TGFBI过表达的促肿瘤活性的机制，我们将把研究重点放在三个具体目标上。 目的1将使用基于人癌细胞的异种移植模型系统完成TGFBI促进转移的活性的表征。 目的2：利用转基因小鼠模型系统研究TGFBI对肿瘤侵袭和转移的影响。 目的3将确定TGFBI通过与特定整合素相互作用激活下游途径的作用机制。 肿瘤发生是一个复杂的多步骤过程。 为了进一步推进我们的知识的分子事件的肿瘤启动和发展，通过肿瘤微环境的变化，新的因素参与这一复杂的病理过程需要确定和表征。 因此，这些研究的完成将进一步了解TGFBI促进肿瘤发生的分子机制，并有助于开发用于治疗人类癌症的新疗法。