TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

Abstract

// Francesca Maddalena 1 , Vittorio Simeon 1 , Giulia Vita 2 , Annamaria Bochicchio 3 , Luciana Possidente 2 , Lorenza Sisinni 1 , Giacomo Lettini 1 , Valentina Condelli 1 , Danilo Swann Matassa 4 , Valeria Li Bergolis 5 , Alberto Fersini 6 , Sante Romito 5 , Michele Aieta 3 , Antonio Ambrosi 6 , Franca Esposito 4 , Matteo Landriscina 1, 5 1 Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 2 Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 3 Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy 6 General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy Correspondence to: Matteo Landriscina, email: matteo.landriscina@unifg.it Franca Esposito, email: franca.esposito@unina.it Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival Received: November 02, 2016     Accepted: January 09, 2017     Published: February 03, 2017 ABSTRACT 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.