1. Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases
- Author
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Kazuya Yamahatsu, Junji Ueda, Yoko Matsuda, Zenya Naito, Eiji Uchida, Toshiyuki Ishiwata, and Murray Korc
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Male ,Cancer Research ,Epithelial-Mesenchymal Transition ,animal structures ,Mice, Nude ,Biology ,Article ,Metastasis ,Cell Movement ,Pancreatic tumor ,Cell Line, Tumor ,Pancreatic cancer ,Genetics ,medicine ,Animals ,Humans ,Protein Isoforms ,Epithelial–mesenchymal transition ,Receptor, Fibroblast Growth Factor, Type 2 ,Molecular Biology ,Cell Proliferation ,Cell growth ,Liver Neoplasms ,EMT ,RNA-Binding Proteins ,Neoplasms, Experimental ,Transfection ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Alternative Splicing ,Epithelial Splicing Regulatory Protein 1 ,embryonic structures ,Cancer cell ,Immunology ,Cancer research ,FGFR-2 IIIb ,FGFR-2 IIIc ,ESRP1 ,Carcinoma, Pancreatic Ductal - Abstract
Epithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1-expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs, but weak in poorly-differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly-differentiated cancers. Increased ESRP1 expression was associated with longer survival by comparison with low-ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion, and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to up-regulate ESRP1 may exert a beneficial therapeutic effect in PDAC.
- Published
- 2013
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