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

被引：20
作者：
Cheong, Jit Kong [1 ,2 ,3 ,4 ,5 ]
Gunaratnam, Lakshman [1 ,2 ,3 ]
Zang, Zhi Jiang [1 ,2 ,3 ,4 ,5 ]
Yang, Christopher M. [4 ,5 ]
Sun, Xiaoming [1 ,2 ,3 ]
Nasr, Susan L. [1 ,2 ,3 ]
Sim, Khe Guan [4 ,5 ]
Peh, Bee Keow [5 ,6 ]
Rashid, Suhaimi Bin Abdul [5 ,6 ]
Bonventre, Joseph V. [1 ,2 ,3 ]
Salto-Tellez, Manuel [5 ,6 ]
Hsu, Stephen I. [1 ,2 ,3 ,4 ,5 ,7 ]
机构：
[1] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA 02115 USA
[4] Natl Univ Singapore, Dept Med, Singapore 119074, Singapore
[5] Natl Univ Singapore Hosp, Singapore 119074, Singapore
[6] Natl Univ Singapore, Dept Pathol, Singapore 119074, Singapore
[7] Univ Florida, Coll Med, Div Nephrol & Hypertens & Renal Transplantat, Gainesville, FL 32610 USA
来源：
JOURNAL OF TRANSLATIONAL MEDICINE | 2009年 / 7卷
关键词：
CELL-CYCLE PROGRESSION; TISSUE MICROARRAYS; BR FAMILY; PROTEIN P34(SEI-1); OVARIAN-CANCER; EXPRESSION; CARCINOMAS; TRANSFORMATION; HYBRIDIZATION; TRANSCRIPTION;
D O I：
10.1186/1479-5876-7-8
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
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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页数：15
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