TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors | springermedicine.com

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Journal of Translational Medicine

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Open Access 01-12-2009 | Research

TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors

Authors: Jit Kong Cheong, Lakshman Gunaratnam, Zhi Jiang Zang, Christopher M Yang, Xiaoming Sun, Susan L Nasr, Khe Guan Sim, Bee Keow Peh, Suhaimi Bin Abdul Rashid, Joseph V Bonventre, Manuel Salto-Tellez, Stephen I Hsu

Published in: Journal of Translational Medicine | Issue 1/2009

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Abstract

Background

Members 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).

Methods

Oncogenic 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.

Results

Overexpression 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.

Conclusion

This 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.

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Title: TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors
Authors: Jit Kong Cheong
Lakshman Gunaratnam
Zhi Jiang Zang
Christopher M Yang
Xiaoming Sun
Susan L Nasr
Khe Guan Sim
Bee Keow Peh
Suhaimi Bin Abdul Rashid
Joseph V Bonventre
Manuel Salto-Tellez
Stephen I Hsu
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2009
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/1479-5876-7-8

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