PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):E2404-13. doi: 10.1073/pnas.1319962111. Epub 2014 May 27.


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.

Keywords: PH domain; everolimus; mTOR; p53; p53 target gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Methylation
  • Genes, Tumor Suppressor*
  • Humans
  • Hyperplasia
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Loss of Heterozygosity*
  • Male
  • Mice
  • Mice, Knockout
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction


  • MEN1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TSSC3 protein
  • Proto-Oncogene Proteins c-akt