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，转化生长因子-β在正常的上皮细胞中具有显著的生长抑制作用，并具有肿瘤抑制作用。肿瘤转化会导致这种生长抑制反应的丧失。人类结肠癌一般对转化生长因子-β生长抑制具有功能性抵抗。结直肠癌对转化生长因子-β的耐药可通过多种机制发生。首先，在28%的人类结肠癌中检测到使转化生长因子-βII型受体(TBRII)失活从而诱导转化生长因子-β耐药的突变。其次，转化生长因子-β受体的表达减少被认为是人类结肠癌转化生长因子-β耐药的机制之一。第三，在人类结肠癌中，Smad2(7%)或Smad4(20%)的失活突变会导致转化生长因子β耐药状态。因此，转化生长因子-β信号元件的功能失活与55%的人类结直肠癌有关。在其他45%的病例中，结肠癌是如何对转化生长因子-β的抗增殖反应产生抵抗力的，目前仍不清楚。最近，我们发现了一条新的WD结构域蛋白条带，它可以单独或与抑制Smad的Smad7协同发挥抑制转化生长因子-β信号转导的作用。Smad7在胰腺癌中表达上调，在45%的乳腺癌和60%的结直肠癌中表达上调。我们假设，在STRAP和Smad7的协同作用下，消除了转化生长因子-β诱导的生长停滞，这为人类结肠癌对转化生长因子-β无反应提供了第四种机制。我们进一步假设，STRAP和Smad7在促进生长和阻断转化生长因子-β肿瘤抑制功能方面的功能协同作用与结直肠癌有关。为了检验这些假说，我们提出了以下具体目标。(1)测定STRAP对Smad7介导的转化生长因子-β抑制生长的阻断作用。(2)确定STRAP和Smad7在ERK1/2激活、p21Cip1下调、细胞增殖和肿瘤发生中的作用。(3)检测STRAP和Smad7在不同分期、不同分级的结直肠癌中的表达，探讨STRAP和Smad7介导的抑制转化生长因子-β的抑癌效应在结直肠癌发生发展中的作用。本研究的长期目标是从分子水平上了解部分结直肠癌对转化生长因子-β肿瘤抑制因子耐药的机制，以及STRAP和Smad7之间的功能协同如何参与从大肠息肉向转移癌的转变。这项研究将增进我们对结直肠癌生物学的了解，这将导致识别新的分子靶点，并应改进治疗和预防策略。

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.