Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer

// Abigail J. Deloria 1 , Doris Hoflmayer 2, 6 , Philip Kienzl 1 , Justyna Łopatecka 1 , Sandra Sampl 1 , Martin Klimpfinger 2 , Tamara Braunschmid 3 , Fabienne Bastian 3 , Lingeng Lu 4 , Brigitte Marian 1 , Stefan Stattner 3, 5 , Klaus Holzmann 1 1 Division of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Austria 2 Department of Pathology and Bacteriology, Social Medical Center South, Kaiser Franz Josef Hospital, Vienna, Austria 3 Department of Surgery, Social Medical Center South, Kaiser Franz Josef Hospital, Vienna, Austria 4 Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, USA 5 Department of Visceral, Transplantation and Thoracic Surgery, Innsbruck, Austria 6 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Klaus Holzmann, email: klaus.holzmann@meduniwien.ac.at Keywords: colorectal cancer, epithelial splicing regulatory protein, microsatellite instability, overall survival, prognostic marker Received: April 25, 2016 Accepted: September 02, 2016 Published: September 16, 2016 ABSTRACT ESRPs are master splice regulators implicated in alternative mRNA splicing programs important for epithelial-mesenchymal transition (EMT) and tumor progression. ESRP1 was identified in some tumors as good or worse predictor of outcome, but in colorectal cancer (CRC) the prognostic value of ESRPs and relation with mesenchymal splice variants is not clear. Here, we studied 68 CRC cases, compared tissue expression of ESRPs with clinical data and with EMT gene splice patterns of conditional CRC cells with deficient ESRP1 expression. Around 72% of patients showed global decreased transcript expression of both ESRPs in tumor as compared to matched non-neoplastic colorectal epithelium. Reduction of ESRP1 in tumor cells was evaluated by immunohistochemistry, associated with microsatellite stability and switch to mesenchymal splice signatures of FGFRs, CD44, ENAH and CTNND1(p120-catenin). Expression of ESRPs was significantly associated with favorable overall survival (log-rank test, P =0.0186 and 0.0408), better than prognostic stratification by tumor staging; and for ESRP1 confirmed with second TCGA cohort (log-rank test, P =0.0435). Prognostic value is independent of the pathological stage and microsatellite instability (ESRP1: HR=0.36, 95%CI 0.15–0.91, P =0.032; ESRP2: HR=0.23, 95%CI 0.08–0.65, P =0.006). Our study supports the role of ESRP1 as tumor suppressor and strongly suggests that ESRPs are candidate markers for early detection, diagnosis, and prognosis of CRC.