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。人结肠癌通常在功能上对TGF-β生长抑制具有抗性。结直肠癌对TGF-β的耐药性可以通过多种机制发生。首先，在所有人类结肠癌中检测到28%的突变，其破坏TGF-β II型受体（TBRII），从而诱导TGF-β抗性。第二，TGF-β受体的表达减少被认为是人结肠肿瘤中TGF-β抗性的机制。第三，Smad 2（7%）或Smad 4（20%）的失活突变导致人类结肠癌中的TGF-β抵抗状态。因此，TGF-β信号传导组分的功能失活与55%的人类结直肠癌相关。在其他45%的病例中，结肠癌如何对TGF-β的抗增殖反应产生耐药性仍然是未知的。最近，我们已经确定了一种新的WD结构域蛋白STRAP，作为TGF-β信号传导的抑制剂，无论是单独还是与抑制性Smad，Smad 7协同作用。Smad 7在胰腺癌中上调，STRAP在45%的乳腺癌和60%的结直肠癌中上调。我们推测，通过STRAP和Smad 7的协同作用消除TGF-β诱导的生长停滞提供了第四种机制，通过该机制人类结肠肿瘤变得对TGF-β无反应。我们进一步假设，在结直肠癌中，STRAP和Smad 7在生长促进作用和阻断TGF-β肿瘤抑制功能方面的功能合作。提出了以下具体目标来检验这些假设。(1)确定STRAP对Smad 7介导的TGF-β生长抑制阻断的作用。(2)确定STRAP和Smad 7在ERK 1/2激活、p21 Cip 1下调、细胞增殖和致瘤性中的作用。(3)检查STRAP和Smad 7在不同阶段和级别的结直肠癌中的表达，并确定STRAP和Smad 7介导的TGF-β肿瘤抑制作用的消除如何参与结直肠肿瘤的发展和进展。本研究的长期目标是在分子水平上了解一部分结直肠癌对TGF-β肿瘤抑制作用产生抗性的机制，以及SRAP和Smad 7之间的功能合作如何参与从结肠息肉到转移性癌的转变。这项研究将提高我们对结直肠癌生物学的理解，这将导致新的分子靶点的鉴定，并应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.