title: PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors.
abstract: The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.
authors.affiliation: Divisions of Refractory Cancer Research, rohki@ncc.go.jp.
authors.forename: Rieko
authors.initials: R
authors.lastname: Ohki
authors.affiliation: Divisions of Refractory Cancer Research,Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;
authors.forename: Kozue
authors.initials: K
authors.lastname: Saito
authors.affiliation: Divisions of Refractory Cancer Research,Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Radiobiology.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kawase
authors.affiliation: Molecular Pathology.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.affiliation: Divisions of Refractory Cancer Research,Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;
authors.forename: Raira
authors.initials: R
authors.lastname: Saigawa
authors.affiliation: Divisions of Refractory Cancer Research,Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;
authors.forename: Maiko
authors.initials: M
authors.lastname: Minegishi
authors.affiliation: Divisions of Refractory Cancer Research.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Aita
authors.affiliation: Department of Organ Reconstruction, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan;
authors.forename: Goichi
authors.initials: G
authors.lastname: Yanai
authors.affiliation: Cancer Genomics, and.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Divisions of Refractory Cancer Research.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan;
authors.forename: Naoaki
authors.initials: N
authors.lastname: Sakata
authors.affiliation: Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.affiliation: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan;
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kosuge
authors.affiliation: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
authors.affiliation: Familial Cancer Research, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tsukada
authors.affiliation: Molecular Pathology.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Organ Reconstruction, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan;
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Sumi
authors.affiliation: Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;
authors.forename: Hideo
authors.initials: H
authors.lastname: Namiki
authors.affiliation: Radiobiology,Cancer Research Center of Excellence, Center for Life Sciences, National University of Singapore, Singapore 117456.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.affiliation: Cancer Genomics, and.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Divisions of Refractory Cancer Research.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019175:DNA Methylation; D016147:Genes, Tumor Suppressor; D006801:Humans; D006965:Hyperplasia; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C105373:MEN1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C109277:TSSC3 protein; D051057:Proto-Oncogene Proteins c-akt
keywords: PH domain; everolimus; mTOR; p53; p53 target gene