title: The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression.
abstract: Pancreatic cancer is an aggressive disease characterized by rapid growth and early metastasis. The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and/or constitutively active in several epithelial cancers, but its role in pancreatic cancer is unknown. In this study, we have characterized RON expression in both murine and human pancreatic cancer. Immunoblotting indicates that RON is expressed in pancreatic intraepithelial neoplasia (PanIN), primary, and metastatic cell lines both in the human and mouse. Immunostaining revealed that 93% of high-grade PanIN, 79% of primary, and 83% of metastatic lesions from human pancreatic tissue samples expressed RON, with minimal expression in normal ducts and low-grade PanIN (6% and 18%, respectively). Moreover, we show a dose-dependent effect of hepatocyte growth factor-like protein (HGFL), the RON-specific ligand, on pancreatic cancer cell migration and invasion, which was reversed by RON inhibition. Although stimulation with HGFL had no effect on proliferation, concurrent RON receptor blockade and gemcitabine treatment increased apoptosis of RON-expressing pancreatic cancer cells versus gemcitabine treatment alone. Finally, HGFL stimulation of pancreatic cancer cells resulted in increased expression of phospho-mitogen-activated protein kinase and phospho-Akt. Taken together, these findings suggest that RON receptor signaling may contribute to pancreatic carcinogenesis, and that further investigation is warranted to assess the potential of RON-directed therapies in this deadly disease.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.forename: Kenya
authors.initials: K
authors.lastname: Toney
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fenoglio-Preiser
authors.forename: Monica P
authors.initials: MP
authors.lastname: Revelo-Penafiel
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000502:physiology*; D015398:Signal Transduction; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D000093542:Gemcitabine