PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors

Rieko Ohki, Kozue Saito, Yu Chen, Tatsuya Kawase, Nobuyoshi Hiraoka, Raira Saigawa, Maiko Minegishi, Yukie Aita, Goichi Yanai, Hiroko Shimizu, Shinichi Yachida, Naoaki Sakata, Ryuichiro Doi, Tomoo Kosuge, Kazuaki Shimada, Benjamin Tycko, Toshihiko Tsukada, Yae Kanai, Shoichiro Sumi, Hideo NamikiYoichi Taya, Tatsuhiro Shibata, Hitoshi Nakagama

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number23
DOIs
Publication statusPublished - 2014 Jun 10
Externally publishedYes

Fingerprint

Neuroendocrine Tumors
Multiple Endocrine Neoplasia Type 1
Neoplasms
Loss of Heterozygosity
Biological Phenomena
Gene Silencing
Methylation
Hyperplasia
Disease Progression
Genes

Keywords

  • Everolimus
  • mTOR
  • p53
  • p53 target gene
  • PH domain

ASJC Scopus subject areas

  • General

Cite this

PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors. / Ohki, Rieko; Saito, Kozue; Chen, Yu; Kawase, Tatsuya; Hiraoka, Nobuyoshi; Saigawa, Raira; Minegishi, Maiko; Aita, Yukie; Yanai, Goichi; Shimizu, Hiroko; Yachida, Shinichi; Sakata, Naoaki; Doi, Ryuichiro; Kosuge, Tomoo; Shimada, Kazuaki; Tycko, Benjamin; Tsukada, Toshihiko; Kanai, Yae; Sumi, Shoichiro; Namiki, Hideo; Taya, Yoichi; Shibata, Tatsuhiro; Nakagama, Hitoshi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 23, 10.06.2014.

Research output: Contribution to journalArticle

Ohki, R, Saito, K, Chen, Y, Kawase, T, Hiraoka, N, Saigawa, R, Minegishi, M, Aita, Y, Yanai, G, Shimizu, H, Yachida, S, Sakata, N, Doi, R, Kosuge, T, Shimada, K, Tycko, B, Tsukada, T, Kanai, Y, Sumi, S, Namiki, H, Taya, Y, Shibata, T & Nakagama, H 2014, 'PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 23. https://doi.org/10.1073/pnas.1319962111
Ohki, Rieko ; Saito, Kozue ; Chen, Yu ; Kawase, Tatsuya ; Hiraoka, Nobuyoshi ; Saigawa, Raira ; Minegishi, Maiko ; Aita, Yukie ; Yanai, Goichi ; Shimizu, Hiroko ; Yachida, Shinichi ; Sakata, Naoaki ; Doi, Ryuichiro ; Kosuge, Tomoo ; Shimada, Kazuaki ; Tycko, Benjamin ; Tsukada, Toshihiko ; Kanai, Yae ; Sumi, Shoichiro ; Namiki, Hideo ; Taya, Yoichi ; Shibata, Tatsuhiro ; Nakagama, Hitoshi. / PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 23.
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AU - Saito, Kozue

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AU - Kawase, Tatsuya

AU - Hiraoka, Nobuyoshi

AU - Saigawa, Raira

AU - Minegishi, Maiko

AU - Aita, Yukie

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AU - Shimizu, Hiroko

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AU - Sakata, Naoaki

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AU - Kosuge, Tomoo

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AU - Tycko, Benjamin

AU - Tsukada, Toshihiko

AU - Kanai, Yae

AU - Sumi, Shoichiro

AU - Namiki, Hideo

AU - Taya, Yoichi

AU - Shibata, Tatsuhiro

AU - Nakagama, Hitoshi

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N2 - 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.

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