Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma.

Autor:	Hijiya N; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan., Tsukamoto Y; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan., Nakada C; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan., Tung Nguyen L; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. Department of Hepatogastroenterology, Military Central Hospital, Hanoi, Vietnam., Kai T; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan., Matsuura K; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan., Shibata K; Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan., Inomata M; Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan., Uchida T; Department of Forensic Medicine, Faculty of Medicine, Oita University, Oita, Japan., Tokunaga A; Department of Human Anatomy, Faculty of Medicine, Oita University, Oita, Japan., Amada K; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan., Shirao K; Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan., Yamada Y; Department of Radiology, Faculty of Medicine, Oita University, Oita, Japan., Mori H; Department of Radiology, Faculty of Medicine, Oita University, Oita, Japan., Takeuchi I; Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan., Seto M; Division of Molecular Medicine, Aichi Cancer Center, Nagoya, Japan., Aoki M; Division of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan., Takekawa M; Division of Cell Signaling and Molecular Medicine, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan., Moriyama M; Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan. mmoriyam@oita-u.ac.jp.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2016 May 01; Vol. 76 (9), pp. 2612-25. Date of Electronic Publication: 2016 Mar 03.
DOI:	10.1158/0008-5472.CAN-15-1846
Abstrakt:	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. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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