Abstract 2412: Epithelial splicing regulatory protein 1 modulates cell growth, migration, and invasion of human pancreatic ductal adenocarcinoma
Authors: Junji Ueda, Yoko Matsuda, Kazuya Yamahatsu, Eiji Uchida, Zenya Naito, Toshiyuki Ishiwata
Journal: Cancer Research (2012)

Abstract Background: Recent studies have shown that epithelial splicing regulatory protein 1 (ESRP1) plays important roles in the epithelial mesenchymal transition of cancer cells via regulating the splicing of several RNAs, including fibroblast growth factor receptor 2 (FGFR2). Previously we reported that the expression of FGFR2IIIb correlates with vascular invasion and liver metastasis of pancreatic ductal adenocarcinoma (PDAC) (Cho, et al. Am J Pathol. 2008), while the expression of FGFR2IIIc correlates with the growth and invasion of PDAC cells (Ishiwata, et al. AACR. 2010). However, the expression and roles of ESRP1 in PDAC have not been well-defined. Methods: We performed immunohistochemical analysis of ESRP1, FGFR2IIIb, and FGFR2IIIc using pancreatic tissue specimens of PDAC (N=52) and non-tumorous pancreatic tissue (N=8). The ESRP1 expression vector and small interference RNA (siRNA) targeting ESRP1 were used to transfect human PDAC cells, and cell growth, morphology, migration, and invasion were analyzed. To clarify the ESRP1-regulating molecules, we performed proteomic analysis of ESRP1-gene-transfected PDAC cells using mass spectrometry. Results: In immunohistochemical analysis, ESRP1 was strongly expressed in the nuclei of PDAC cells in well- and moderately differentiated adenocarcinoma, while weakly expressed in poorly differentiated adenocarcinoma and normal pancreatic ducts. Well-moderately differentiated adenocarcinomas showed high-FGFR2IIIb/low-FGFR2IIIc pattern, with opposite for poorly differentiated adenocarcinoma. The overall and disease-free survival rates of the high-ESRP1 group were significantly than those of the low-ESRP1 group. In vitro, transient transfection of PDAC cells with ESRP1 expression vector led to an increase in FGFR2IIIb expression and decrease in migration and invasion. Stable transfection of PDAC cells with the ESRP1 expression vector resulted in an increase of FGFR2IIIb expression and decrease in migration and invasion. In contrast, ESRP1 siRNA-transfected PDAC cells induced FGFR2IIIc expression and increased cell growth, migration, and invasion. In proteomic analysis, transiently ESRP1 transfected PDAC cells showed a decreased expression of vimentin, 14-3-3 protein epsilon, heat shock protein 70, and the IQ motif containing GTPase activating protein 1, but an increased expression of filamin alpha. Several proteins as determined by proteomic analysis are involved in cell growth, migration, and invasion. Conclusion: The expression of ESRP1 correlates with the differentiation and prognosis of PDAC, and it modulates cell growth, migration, and invasion in PDAC cells via the alternation of several proteins including FGFR2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2412. doi:1538-7445.AM2012-2412