TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

• Published in: Oncotarget 2017-03, Vol.8 (13), p.21229-21240
• Main Authors: Maddalena, Francesca, Simeon, Vittorio, Vita, Giulia, Bochicchio, Annamaria, Possidente, Luciana, Sisinni, Lorenza, Lettini, Giacomo, Condelli, Valentina, Matassa, Danilo Swann, Li Bergolis, Valeria, Fersini, Alberto, Romito, Sante, Aieta, Michele, Ambrosi, Antonio, Esposito, Franca, Landriscina, Matteo
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Aged; Aged, 80 and over; Biomarkers, Tumor - analysis; Cluster Analysis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Disease-Free Survival; Female; Gene Dosage; HSP90 Heat-Shock Proteins - biosynthesis; HSP90 Heat-Shock Proteins - genetics; Humans; Immunoblotting; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Research Paper; Transcriptome; Up-Regulation
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.15070

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.