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.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men and second in women worldwide [1]
This study investigates ESRP1 and 2 expression as well as alternative splicing patterns in paired tumor and non-tumor tissue of colorectal cancer (CRC) patients and their correlation with clinical data
The results demonstrate a co-expression of both paralogs and indicate that expression of Epithelial splicing regulatory proteins (ESRPs) in tumor is associated with a prolonged overall survival
Summary
Colorectal cancer (CRC) is the third most common cancer in men and second in women worldwide [1]. FGFR1-4 signaling pathways are activated upon FGF ligand binding and regulate important biological processes such as tissue development, regeneration, angiogenesis, and cancer. FGFRs are highly subjected to alternative splicing, especially its Ig-like III domain with IIIb and IIIc variants observed in FGFR1-3 [6, 7]. This domain plays a critical role as it determines ligand binding specificity. The IIIb and IIIc variants are tissue-specific, such that the former is preferentially www.impactjournals.com/oncotarget expressed in epithelial and the latter in mesenchymal cells. FGFR2 IIIc variant was recently identified to drive EMT in epithelial cells [9]
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