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.p53 | PH domain | everolimus | p53 target gene | mTOR N euroendocrine tumors (NETs) arise from cells of the endocrine and nervous systems, and are found in tissues such as lung, pancreas and pituitary (1-3). NETs often produce, store and release biogenic amines and polypeptide hormones, and secretary granules containing these products provide a diagnostic marker for NETs. The mechanisms underlying the development of NETs remain unclear to date, due to the low incidence of these tumors and due to the lack of suitable experimental model systems, including genetically engineered mouse models. Pancreatic NET (PanNET), which is probably the best-studied NET, is the second-most common pancreatic tumor, having an incidence of ∼1 per 100,000 individuals. Patients having late-stage PanNET often harbor tumors that are unresectable or metastatic and face limited treatment options. Accordingly, the prognosis of patients having metastatic PanNET is the worst among the NET subtypes, with a 5-y survival rate of 27-43% (1). Recently, the drug Everolimus has shown promise in the treatment of PanNETs (4), providing a significant improvement in progression-free survival. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a downstream mediator of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. The striking efficacy of Everolimus demonstrates the importance of the PI3K/Akt pathway in the pathology of PanNETs.In agreement with these clinical results, studies on pancreatic endocrine cell lines have identified the PI3K/Akt signaling pathway as a major proliferation and survival pathway in these cells (5). Activated Akt phosphorylates substrates such as mTOR and controls various biological processes, including protein synthesis, proliferation, cell growth, and survival. Regulation of pancreatic islet β-cell proliferation, cell size, and apoptosis by Akt has been demonstrated using various mouse models. For examp...

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

“…Hypoxia-induced p53-mediated apoptosis could therefore be a crucial component of tumor suppression. In support of this hypothesis, some of the hypoxia-inducible p53 targets, such as PHLDA3 and KANK3, have already been linked with p53-mediated tumor suppression (23,46). By carrying out thorough and independent analyses of large clinical cohorts of breast and other cancers, we found that poor patient prognosis and progression of disease are significantly and consistently associated with diminished expression of the hypoxia-inducible p53-dependent group of genes, suggesting that their function is lost in aggressive cancers.…”

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…Loss of heterozygosity studies in PanNET indicate loss of 22q12.1 (75%), 3p23 (74%), 11q13 (67%; Men1), 6p22 (62%), 10q23 (50%: PTEN). Ohki and coworkers recently reported that the genomic region of the PHLDA3 gene (1q31) undergoes LOH in 75% of PanNET, and they could correlate this event with disease progression and adverse prognosis (Ohki et al 2014). PHLDA3 locus undergoes methylation in addition …”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Two additional studies (Kimura et al 2016, Vijayvergia et al 2016) confirmed mutations in KRAS and TP53. PHLDA3, a pleckstrin homology-like protein, which is a potent inhibitor of AKT activation (Kawase et al 2009), is inactivated in 72% of pNET patients due to PHLDA3 gene loss of heterozygosity (Ohki et al 2014).…”