Repression of the Akt pathway by a novel tumor suppressor gene PHLDA3 -towards development of tailor-made therapies-

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Pancreatic neuroendocrine tumors (PanNETs) are a rare pathology and molecular mechanisms underlying their development have not been well defined. We showed that a 2-hit inactivation of the PHLDA3 gene is required for PanNET development: methylation of the locus and loss of heterozygosity. PHLDA3 functions as a suppressor of PanNETs via repression of Akt activity and downstream Akt-regulated biological processes. In addition, the tumor-suppressing pathway mediated by MEN1, a well-known suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs is demonstrated, and the findings may contribute to personalized medicine of PanNET patients.