TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumorsReportar como inadecuado




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Journal of Translational Medicine

, 7:8

First Online: 20 January 2009Received: 15 May 2008Accepted: 20 January 2009DOI: 10.1186-1479-5876-7-8

Cite this article as: Cheong, J.K., Gunaratnam, L., Zang, Z.J. et al. J Transl Med 2009 7: 8. doi:10.1186-1479-5876-7-8

Abstract

BackgroundMembers of the TRIP-Br-SERTAD family of mammalian transcriptional coregulators have recently been implicated in E2F-mediated cell cycle progression and tumorigenesis. We, herein, focus on the detailed functional characterization of the least understood member of the TRIP-Br-SERTAD protein family, TRIP-Br2 SERTAD2.

MethodsOncogenic potential of TRIP-Br2 was demonstrated by 1 inoculation of NIH3T3 fibroblasts, which were engineered to stably overexpress ectopic TRIP-Br2, into athymic nude mice for tumor induction and 2 comprehensive immunohistochemical high-throughput screening of TRIP-Br2 protein expression in multiple human tumor cell lines and human tumor tissue microarrays TMAs. Clinicopathologic analysis was conducted to assess the potential of TRIP-Br2 as a novel prognostic marker of human cancer. RNA interference of TRIP-Br2 expression in HCT-116 colorectal carcinoma cells was performed to determine the potential of TRIP-Br2 as a novel chemotherapeutic drug target.

ResultsOverexpression of TRIP-Br2 is sufficient to transform murine fibroblasts and promotes tumorigenesis in nude mice. The transformed phenotype is characterized by deregulation of the E2F-DP-transcriptional pathway through upregulation of the key E2F-responsive genes CYCLIN E, CYCLIN A2, CDC6 and DHFR. TRIP-Br2 is frequently overexpressed in both cancer cell lines and multiple human tumors. Clinicopathologic correlation indicates that overexpression of TRIP-Br2 in hepatocellular carcinoma is associated with a worse clinical outcome by Kaplan-Meier survival analysis. Small interfering RNA-mediated siRNA knockdown of TRIP-Br2 was sufficient to inhibit cell-autonomous growth of HCT-116 cells in vitro.

ConclusionThis study identifies TRIP-Br2 as a bona-fide protooncogene and supports the potential for TRIP-Br2 as a novel prognostic marker and a chemotherapeutic drug target in human cancer.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-7-8 contains supplementary material, which is available to authorized users.

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Autor: Jit Kong Cheong - Lakshman Gunaratnam - Zhi Jiang Zang - Christopher M Yang - Xiaoming Sun - Susan L Nasr - Khe Guan S

Fuente: https://link.springer.com/







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