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 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.
1] Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan [2] Department of Surgery for Organ and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
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J
Ueda
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
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Y
Matsuda
1] Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan [2] Department of Surgery for Organ and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
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K
Yamahatsu
Department of Surgery for Organ and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
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E
Uchida
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
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Z
Naito
Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
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M
Korc
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
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T
Ishiwata
D017398:Alternative Splicing; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism
C539364:ESRP1 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2