Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases

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 analy...

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Bibliographic Details
Published in:	Oncogene Vol. 33; no. 36; pp. 4485 - 4495
Main Authors:	Ueda, J, Matsuda, Y, Yamahatsu, K, Uchida, E, Naito, Z, Korc, M, Ishiwata, T
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-09-2014 Nature Publishing Group
Subjects:	631/45/612/1230 692/699/67/1504/1713 692/699/67/322 Adenocarcinoma Alternative Splicing Animals Apoptosis Binding proteins Cancer Carcinoma, Pancreatic Ductal - diagnosis Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cell Biology Cell differentiation Cell growth Cell Line, Tumor Cell migration Cell Movement Cell Proliferation Complications and side effects Epithelial-Mesenchymal Transition Fibroblast growth factor receptors Gene Expression Regulation, Neoplastic Genetic aspects Human Genetics Humans Immunohistochemistry Immunoreactivity Internal Medicine Isoforms Liver Neoplasms - pathology Liver Neoplasms - secondary Male Medicine Medicine & Public Health Metastases Metastasis Mice, Nude Neoplasms, Experimental Oncology original-article Pancreatic cancer Pancreatic Neoplasms - diagnosis Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Prevention Properties Protein Isoforms - genetics Protein Isoforms - metabolism Proteins Receptor, Fibroblast Growth Factor, Type 2 - genetics Receptor, Fibroblast Growth Factor, Type 2 - metabolism RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism RNA-mediated interference siRNA Tumors pancreatic cancer FGFR-2 IIIb FGFR-2 IIIc EMT ESRP1
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Summary:	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 in 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 upregulate ESRP1 may exert a beneficial therapeutic effect in PDAC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2013.392