This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Colorectal cancer has been associated with alterations in the TGF-b signal transduction pathways. Prospective studies have positively correlated the circulating levels of TGF-b1 with poor prognosis in these patients. African Americans have the highest incidence and mortality rates from colorectal cancer among U.S. ethnic and racial groups. Data available suggests that this disparity could be, at least in part, due to differences in biological factors. TGF-b has a predominant growth-inhibitory effect and serves a tumor suppressor role. Neoplastic transformation results in loss of this normal growth-inhibitory response and, under selected conditions, TGF-b may actually promote tumorigenesis. Inactivating mutations of TGF-b receptors and selected TGF-b signal transduction proteins (Smad family proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. Little is known about the regulation and cross-talk between TGF-b and other transcriptional pathways frequently involved in colon cancer. Specifically, NF-kB has been found to be constitutively active in colon cancer cells. It is believed that NF-kB activation protects cancer cells from apoptosis induced by chemotherapeutic agents. Our preliminary results indicate that TGF-b increases the translocation of NF-kB into the nucleus. The mechanisms involved are not clearly understood. However, our results show that TGF-b increases RhoB protein in colon cancer cells. Rho proteins, monomeric GTPases that transduce mitogenic and survival signals from the cell surface to the nucleus, have been implicated in the activation of NFkB.
The aims are to determine the role of TGF-b1 and TGF-b ?signal transduction pathway in regulating the activation of NF-kB and RhoB in colorectal cancer cell lines. To pursue this aim we will treat colon cancer cell lines with TGF-b and/or inhibitors of rhoB and/or stable transfectants of smads and RhoB to assess activation of NF-kB and the regulation of apoptosis. To determine the relative relevance of these pathways in African-Americans compared to Whites, immunohistochemical study of archival tissue from Black and White colon cancer patients will be performed. Understanding the mechanisms involved in colorectal cancer among different ethnic groups will allow us to tailor treatment options to specific molecular abnormalities.
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