STRAP and Smad 7 Signaling in Colerectal Carcinomas

描述（由申请人提供）：有令人信服的证据表明tgf - β在正常上皮细胞中具有主要的生长抑制作用，并可作为肿瘤抑制因子。肿瘤转化导致这种生长抑制反应的丧失。人类结肠癌通常对tgf - β生长抑制具有功能抗性。结直肠癌中对tgf - β的抵抗可以通过多种机制发生。首先，在28%的人类结肠癌中发现了使tgf - β II型受体（TBRII）失活从而诱导tgf - β耐药的突变。其次，tgf - β受体的表达减少被认为是人类结肠肿瘤中tgf - β耐药的机制之一。第三，Smad2（7%）或Smad4（20%）失活突变导致人类结肠癌中tgf - β耐药状态。因此，tgf - β信号成分的功能失活与55%的人类结直肠癌有关。目前尚不清楚在另外45%的病例中，结肠癌是如何对tgf - β的抗增殖反应产生耐药性的。最近，我们发现了一种新的wd结构域蛋白STRAP，它可以单独或与抑制Smad， Smad7协同作用，作为tgf - β信号传导的抑制剂。Smad7在胰腺癌中表达上调，而STRAP在45%的乳腺癌和60%的结直肠癌中表达上调。我们假设，通过STRAP和Smad7的协同作用消除tgf - β诱导的生长停滞，提供了人类结肠肿瘤对tgf - β无反应的第四种机制。我们进一步假设，STRAP和Smad7在促进生长和阻断tgf - β肿瘤抑制功能方面的功能合作参与了结直肠癌的发生。提出以下具体目标来检验这些假设。(1)确定STRAP在smad7介导的tgf - β生长抑制阻断中的作用。(2)确定STRAP和Smad7在ERK1/2激活、p21Cip1下调、细胞增殖和致瘤性中的作用。(3)检测STRAP和Smad7在结直肠癌不同分期和分级中的表达，确定STRAP和Smad7介导的tgf - β肿瘤抑制作用的解除在结直肠癌发生发展中的作用。本研究的长期目标是在分子水平上了解部分结直肠癌对tgf - β肿瘤抑制作用产生耐药性的机制，以及STRAP和Smad7之间的功能合作如何参与结肠息肉向转移性癌的转变。这项研究将增强我们对结直肠癌生物学的认识，从而发现新的分子靶点，并改善治疗和预防策略。

DESCRIPTION (provided by applicant): There is compelling evidence indicating that TGF-beta has a predominant growth inhibitory effect in normal epithelial cells and serves as a tumor suppressor. Neoplastic transformation results in loss of this growth inhibitory response. Human colon cancers are in general functionally resistant to TGF-beta growth inhibition. Resistance to TGF-betas in colorectal cancers can occur through a variety of mechanisms. First, mutations that inactivate TGF-beta type II receptor (TBRII) and thereby induce TGF-beta resistance are detected in 28% of all human colon cancers. Second, reduced expression of the TGF-beta receptors has been implicated as a mechanism for TGF-beta resistance in human colon tumors. Third, inactivating mutations of either Smad2 (7%) or Smad4 (20%) lead to a TGF-beta resistant state in human colon cancers. Therefore, functional inactivation of TGF-beta signaling components is associated with 55% of human colorectal cancers. It is still unknown how colon cancers become resistant to the antiproliferative response to TGF-beta in the other 45% of cases. Recently, we have identified a novel WD-domain protein STRAP that functions as an inhibitor of TGF-beta signaling, both alone and synergistically with the inhibitory Smad, Smad7. Smad7 is upregulated in pancreatic cancer, and STRAP is upregulated in 45% of breast cancers and in 60% of colorectal cancers. We hypothesize that abrogation of TGF-beta-induced growth arrest by the synergistic effects of STRAP and Smad7 provides a fourth mechanism by which human colon tumors become non-responsive to TGF-beta. We further hypothesize that functional cooperation between STRAP and Smad7 in growth promoting effects, and in blocking TGF-beta tumor suppressor function, is involved in colorectal carcinomas. The following specific aims are proposed to test these hypotheses. (1) Determine the role of STRAP on Smad7-mediated blockade of grown inhibition by TGF-beta. (2) Determine the roles of STRAP and Smad7 in ERK1/2 activation, in p21Cip1 downregulation, in cellular proliferation, and in tumorigenicity. (3) Examine the expression of STRAP and Smad7 in different stages and grades of colorectal cancer, and determine how STRAP- and Smad7-mediated abrogation of TGF-beta tumor suppressor effects is involved in colorectal tumor development and progression. The long term objectives of this study are to understand, at the molecular level, the mechanism by which a portion of colorectal cancers become resistant to TGF-beta tumor suppressor effects, and how functional cooperation between STRAP and Smad7 is involved in the transition from colonic polyp to metastatic carcinoma. This study will enhance our understanding of colorectal cancer biology, which will lead to the identification of new molecular targets, and should improve treatment and prevention strategies.