title: Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma.
abstract: The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. ©2016 AACR.
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hijiya
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakada
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. Department of Hepatogastroenterology, Military Central Hospital, Hanoi, Vietnam.
authors.forename: Lam
authors.initials: L
authors.lastname: Tung Nguyen
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kai
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inomata
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Human Anatomy, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Tokunaga
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Amada
authors.affiliation: Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.affiliation: Department of Radiology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Radiology, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.affiliation: Division of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Division of Cell Signaling and Molecular Medicine, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Mutsuhiro
authors.initials: M
authors.lastname: Takekawa
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. mmoriyam@oita-u.ac.jp.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Moriyama
mesh_terms: D065311:Adenocarcinoma in Situ / Q000235:genetics / Q000473:pathology*; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D018613:Microscopy, Confocal; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D059467:Transcriptome
chemical_list: D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases