P-239 - Prognostic role of TRAP1 protein network in human metastatic colorectal carcinoma

Abstract

Introduction: Background. Colorectal cancer (CRC) is a molecularly heterogeneous disease with high mortality rate. Since drug resistance is the limiting factor for successful treatment of patients in metastatic setting, the identification of prognostic and predictive factors for therapy selection is a major clinical need. We previously characterized the biological relevance of TRAP1, a molecular chaperone belonging to HSP90 family, upregulated in 50-60% of human colorectal carcinomas (CRCs). In particular, TRAP1 is involved in control of several tumor cellular functions as intracellular signaling, cell cycle, apoptosis, stemness and bioenergetics through co-translational regulation of a network of client proteins (i.e., F1ATPase, TBP7, IF2α, EF1G, IF4A, IF4E, EF1A, BRAF, AKT, 18kDa Sorcin, CDK1/2, MAD2, βCatenin). Nevertheless, the prognostic significance of TRAP1 in CRC is still unclear and needs further investigation. Thus, the clinical and biological significance of TRAP1 and its protein network was analyzed in human CRCs. Methods: Materials and Methods. The expression levels of TRAP1 and/or its client proteins were quantified by immunoblot analysis in 60 surgical specimens of CRCs at different stages and in adjacent noncancerous mucosas and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic CRCs (mCRC). The association between TRAP1 protein network and clinical and pathological characteristics were analyzed. Results: Results. TRAP1 upregulation represents an early event in colorectal carcinogenesis, being increased at the transition between low- and high-grade adenomas, in in situ carcinomas and in about 60% CRCs. Indeed, a significant association was observed between TRAP1 protein level and its gene copy number in a subgroup of colorectal tumors (data from the TCGA database). Furthermore, TRAP1 was co-upregulated with its network of client proteins (i.e., TBP7, p-IF2α, IF2α, eF1G, iF4A, IF4E, eF1A, BRAF, CDK1/2, MAD2 and βCatenin) in 60 human CRCs. Indeed, Spearman Rank correlation test showed a significant co-expression between TRAP1 and several client proteins, independently from tumor grade and stage. Noteworthy, the hierarchical cluster analysis of mCRCs identified a cohort of tumors with upregulation of a 7-protein TRAP1 signature (i.e., TRAP1, IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) and a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p = 0.037). Consistently, TRAP1 prognostic value was confirmed in a validation cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value were more evident in left colon cancers. Conclusion: This study provides the first comprehensive proteomic evaluation of TRAP1 protein network in colorectal tumors, showing the clinical relevance of its activation as a mechanism to coordinate a number of signaling pathway responsible for tumor progression and clinical aggressiveness.