Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer.
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.
['Deloria|Abigail J|AJ|', 'Höflmayer|Doris|D|', 'Kienzl|Philip|P|', 'Łopatecka|Justyna|J|', 'Sampl|Sandra|S|', 'Klimpfinger|Martin|M|', 'Braunschmid|Tamara|T|', 'Bastian|Fabienne|F|', 'Lu|Lingeng|L|', 'Marian|Brigitte|B|', 'Stättner|Stefan|S|', 'Holzmann|Klaus|K|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D045744:Cell Line, Tumor D015179:Colorectal Neoplasms D005260:Female D015870:Gene Expression D006801:Humans D007150:Immunohistochemistry D053208:Kaplan-Meier Estimate D008297:Male D053842:Microsatellite Instability D008875:Middle Aged D060787:Neoplasm Grading D009367:Neoplasm Staging D011379:Prognosis D016016:Proportional Hazards Models D012326:RNA Splicing D016601:RNA-Binding Proteins
epithelial splicing regulatory protein colorectal cancer overall survival microsatellite instability prognostic marker