STRAP and Smad 7 Signaling in Colorectal Carcinomas

描述（由申请人提供）：结直肠癌发生涉及遗传和表观遗传变化的积累，导致正常结直肠上皮改变、原位癌，最终导致浸润性和转移性癌症。 TGF-β诱导的肿瘤抑制功能的丧失在这种转变中起着关键作用。 结直肠癌对TGF-β的耐药性可以通过多种机制发生。 然而，TGF-β II型受体和选定的TGF-β信号转导子（Smad 2/4）的失活突变以及受体表达的减少不足以（约55%）解释癌中TGF-β不敏感的高频率。 在其他病例中（约45%），结肠癌如何对TGF-β的抗增殖反应产生耐药性仍是未知数。 我们鉴定了一种新的WD结构域蛋白STRAP（丝氨酸苏氨酸激酶受体相关蛋白），其与TGF-β受体复合物和Smad 7结合，并抑制TGF-β信号传导。 我们已经报道了STRAP和Smad 7在结直肠癌中上调，刺激细胞生长，诱导锚定非依赖性生长并增强致瘤性。 我们的初步数据表明，STRAP诱导上皮间充质转化（EMT）通过去调节E-钙粘蛋白独立的TGF-β。 STRAP还增加了可能有助于细胞增殖的claudin 1和CyclinD 1的表达。 我们有证据表明，STRAP上调活性MMP 9和纤连蛋白，并诱导细胞迁移和侵袭。 此外，我们已经证明，在结肠癌细胞中稳定表达Smad 7诱导转移。 基于背景信息，我们提出了以下假设：STRAP消除TGF-β诱导的生长抑制，以及STRAP的非TGF-β依赖性效应，包括诱导细胞增殖、EMT、迁移和侵袭，对于结直肠癌恶性表型的获得至关重要。 我们进一步假设，STRAP和Smad 7在阻断TGF-β肿瘤抑制功能方面的功能合作参与了结肠肿瘤的进展和转移。 这些假设将通过以下具体目的进行检验：1）确定STRAP促进上皮向间充质转化（EMT）的机制。 2)确定STRAP调节癌细胞增殖、迁移和侵袭的TGF-β依赖和非依赖机制。 3)确定SRAP和Smad 7之间的功能合作如何有助于结肠肿瘤转移以及人类结直肠癌中SRAP上调的机制。 本研究的长期目标是在分子水平上了解结直肠肿瘤对TGF-β肿瘤抑制作用产生抗性的机制。 更好地了解EMT、迁移、侵袭和转移的调节因子将有助于改善药物开发和大肠癌的治疗。

DESCRIPTION (provided by applicant): Colorectal carcinogenesis involves an accumulation of genetic and epigenetic changes that lead to alterations in normal colorectal epithelium, in situ carcinoma, and finally invasive and metastatic cancers. The loss of TGF-¿-induced tumor suppressor function plays a pivotal role in this transition. Resistance to TGF-¿ in colorectal cancers can occur through a variety of mechanisms. However, inactivating mutations in the TGF-¿ type II receptor and selected TGF-¿ signal transducers (Smad2/4), and reduced expression of receptors are not enough (around 55%) to account for the high frequency of TGF-¿ insensitivity among carcinomas. It is still unknown how colon cancers become resistant to the antiproliferative responses to TGF-¿ in the other (approximately 45%) cases. We identified a novel WD-domain containing protein STRAP (Serine Threonine Kinase Receptor Associated Protein) that binds with both TGF-¿ receptor complex and Smad7, and that inhibits TGF-¿ signaling. We have reported that STRAP and Smad7 are upregulated in colorectal cancers, stimulate cell growth, induce anchorage-independent growth and enhance tumorigenicity. Our preliminary data suggest that STRAP induces epithelial-to-mesenchymal transition (EMT) by deregulating E-cadherin independently of TGF-¿. STRAP also increases the expression of claudin1 and CyclinD1 that may contribute to cell proliferation. We have evidence that STRAP upregulates active MMP9 and fibronectin, and induces cell migration and invasion. In addition, we have demonstrated that stable expression of Smad7 in colon cancer cells induces metastasis. Based on the background information, we have developed the following hypotheses: Abrogation of TGF-¿-induced growth inhibition by STRAP, and TGF-¿-independent effects of STRAP including induction in cell proliferation, EMT, migration and invasion are critical for the acquisition of malignant phenotype in colorectal cancer. We further hypothesize that functional cooperation between STRAP and Smad7 in blocking TGF-¿ tumor suppressor function is involved in colon tumor progression and metastasis. These hypotheses will be tested by following specific aims: 1) Determine the mechanism by which STRAP promotes epithelial-to-mesenchymal transition (EMT). 2) Determine the TGF-¿-dependent and -independent mechanism of STRAP-regulation of cancer cell proliferation, migration and invasion. 3) Determine how functional cooperation between STRAP and Smad7 contributes to colon tumor metastasis and the mechanism of upregulation of STRAP in human colorectal cancer. The long-term objective of this study is to understand, at the molecular level, the mechanism by which colorectal tumors become resistant to TGF-¿ tumor suppressor effects. A better understanding of the regulators of EMT, migration, invasion and metastasis will help to improve drug development and treatment of colorectal cancer.