ArticleProceedings of the National Academy of Sciences of the United States of America2014
PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 104 citations in OpenAlex.
- Article
- Metformin suppresses MEN1-associated pancreatic and pituitary neuroendocrine tumors: evidence from mouse models and clinical data.Endocrine-related cancer · 2026Article
- Review
- Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP/TAZ-p73 pathway.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma.European journal of medical research · 2024Article
- Multiomics Analysis of the PHLDA Gene Family in Different Cancers and Their Clinical Prognostic Value.Current issues in molecular biology · 2024Article
- Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.International journal of molecular sciences · 2024Review
- Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors.Cell death & disease · 2023Article
- Characterizing the role of Phlda3 in the development of acute toxicity and malignant transformation of hematopoietic cells induced by total-body irradiation in mice.Scientific reports · 2023Article
- The role of DNA methylation in human pancreatic neuroendocrine tumours.Endocrine oncology (Bristol, England) · 2023Review
- The link between menin and pleiotrophin in the tumor biology of pancreatic neuroendocrine neoplasms.Cancer science · 2022Article
- Pleckstrin homology-like domain family A, member 3, a miR-19a-3p-regulated gene, suppresses tumor growth in osteosarcoma by downregulating the Akt pathway.Bioengineered · 2022Article
- Cancer-Associated Fibroblasts and Squamous Epithelial Cells Constitute a Unique Microenvironment in a Mouse Model of Inflammation-Induced Colon Cancer.Frontiers in oncology · 2022Article
- Review
- Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms.International journal of molecular sciences · 2021Review
- PHLDA3 promotes lung adenocarcinoma cell proliferation and invasion via activation of the Wnt signaling pathway.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- Puma- and Caspase9-mediated apoptosis is dispensable for p53-driven neural crest-based developmental defects.Cell death and differentiation · 2021Article
- PHLDA3 inhibition attenuates endoplasmic reticulum stress-induced apoptosis in myocardial hypoxia/reoxygenation injury by activating the PI3K/AKT signaling pathway.Experimental and therapeutic medicine · 2021Article
- Signaling Nodes Associated with Endoplasmic Reticulum Stress during NAFLD Progression.Biomolecules · 2021Review
- The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma.Journal of thoracic disease · 2021Article
Corrections and comments
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Authors and funding
23 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.