― 242 ―a recovery of PHLDA3 expression, confirming that DNA methylation is a key regulatory mechanism of its silencing. These findings identify PHLDA3 as a novel tumor suppressor gene with potential implications for PanNETs development. Building on the identification of PHLDA3 as a two-hit inactivated tumor suppressor in PanNETs, studies reported a connection between this gene and the tumor MEN1 mutations and LOH are frequently observed in PanNETs. Interestingly, we found that LOH analysis demonstrated a comparable frequency of LOH for the MEN1 gene (67%) compared to PHLDA3 (72%). Furthermore, a significant proportion of PanNETs displayed LOH at both the PHLDA3 and MEN1 loci, suggesting these genes do not function in the same linear pathway (Fig. 3B, C) 12).AcknowledgmentsI would like to express my sincere gratitude to the Chugai Foundation for Innovative Drug Discovery Science (C-FINDs) for their generous financial support through a research scholarship. Their support was essential in enabling the successful completion of this study.References1. 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., ... Nakagama, H.: PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors. Proceedings of the National Academy of Sciences of the United States of America, 111(23), E2404–E2413 (2014).2. Kawase, T., Ohki, R., Shibata, T., Tsutsumi, S., Kamimura, N., Inazawa, J., Ohta, T., Ichikawa, H., Aburatani, H., Tashiro, F., & Taya, Y.: PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell, 136(3), 535–550 (2009). https://doi.org/10.1016/j.cell.2008.12.002.3. Takikawa, M., & Ohki, R.: A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors. Cancer Science, 108(6), 1101–1108 (2017). https://doi.org/10.1111/cas.132354. Lebastchi, A. H., & Callender, G. G.: Thyroid cancer. Current Problems in Cancer, 38(2), 48–74 (2014). https://doi.org/10.1016/j.currproblcancer.2014.04.001.5. Madhuchhanda, R., Herbert, C., Rebecca, S. S.: Current Understanding and Management of Medullary Thyroid Cancer. Oncologist, 2013 Sep 13;18(10):1093–1100. https://doi.org/10.1634/theoncologist.2013-0053.6. Takahashi, C., Contreras, B., Iwanaga, T., Takegami, Y., Bakker, A., Bronson, R. T., Noda, M., Loda, M., Hunt, J. L., & Ewen, M. E.: Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Nature Genetics, 38, 118–123 (2006). https://doi.org/10.1038/ng1709.7. Feroz, W., & Sheikh, A.: Exploring the multiple roles of guardian of the genome: P53. Egyptian Journal of Medical Human Genetics, 21, 49 (2020). https://doi.org/10.1186/s43042-020-00091-2.8. Chen, J.: The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harbor Perspectives in Medicine, 6(3), a026104 (2016). https://doi.org/10.1101/cshperspect.a0261049. Chen, Y., & Ohki, R.: p53-PHLDA3-AKT network: The key regulators of neuroendocrine tumorigenesis. International Journal of Molecular Sciences, 21(11), 4098 (2020). https://doi.org/10.3390/ijms21114098.10. Yang YM, Liu TH, Chen YJ, Jiang WJ, Qian JM, Lu X, Chen J.: Chromosome 1q loss of heterozygosity
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