PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors
| Autor: | Ryuichiro Doi, Rieko Ohki, Maiko Minegishi, Tomoo Kosuge, Tatsuhiro Shibata, Yae Kanai, Shinichi Yachida, Tatsuya Kawase, Toshihiko Tsukada, Benjamin Tycko, Naoaki Sakata, Raira Saigawa, Kozue Saito, Goichi Yanai, Yoichi Taya, Hideo Namiki, Kazuaki Shimada, Hitoshi Nakagama, Hiroko Shimizu, Nobuyoshi Hiraoka, Shoichiro Sumi, Yu Chen, Yukie Aita |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Blotting Western Loss of Heterozygosity Apoptosis Biology Neuroendocrine tumors law.invention Loss of heterozygosity Islets of Langerhans Mice law Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans MEN1 Genes Tumor Suppressor Rats Wistar Protein kinase B Cells Cultured Mice Knockout geography Multidisciplinary geography.geographical_feature_category Hyperplasia Reverse Transcriptase Polymerase Chain Reaction Nuclear Proteins Methylation DNA Methylation medicine.disease Islet Prognosis Rats Pancreatic Neoplasms Neuroendocrine Tumors PNAS Plus Rats Inbred Lew Cancer research Suppressor Proto-Oncogene Proteins c-akt |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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