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.
The loss of transforming growth factor-? (TGF-?)-induced tumor suppressor function in tumors plays a pivotal role in the transition from normal colorectal epithelium, to in situ carcinoma, and finally invasive and metastatic colorectal cancer progression and metastasis. A better understanding of these mechanisms will help to improve drug development and treatment of this lethal disease.
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