TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma
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Francesca Maddalena1, Vittorio Simeon1, Giulia Vita2, Annamaria Bochicchio3, Luciana Possidente2, Lorenza Sisinni1, Giacomo Lettini1, Valentina Condelli1, Danilo Swann Matassa4, Valeria Li Bergolis5, Alberto Fersini6, Sante Romito5, Michele Aieta3, Antonio Ambrosi6, Franca Esposito4, Matteo Landriscina1,5
1Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
2Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
3Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
4Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
5Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
6General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
Matteo Landriscina, email: [email protected]
Franca Esposito, email: [email protected]
Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival
Received: November 02, 2016 Accepted: January 09, 2017 Published: February 03, 2017
TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors. TRAP1 is upregulated at the transition between low- and high-grade adenomas, in in situ carcinomas and in about 60% of human colorectal carcinomas, being downregulated only in a small cohort of tumors. The analysis of TCGA database showed that a subgroup of colorectal tumors is characterized by gain/loss of TRAP1 copy number, this correlating with its mRNA and protein expression. Interestingly, TRAP1 is co-expressed with the majority of its client proteins and hierarchical cluster analysis showed that the upregulation of TRAP1 and associated 6-protein signature (i.e., IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) identifies a cohort of metastatic colorectal carcinomas with a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p=0.037). Consistently, the prognostic relevance of TRAP1 was confirmed in a cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value are more evident in left colon cancers. These data suggest that TRAP1 protein network may provide a prognostic signature in human metastatic colorectal carcinomas.
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