Fig 1．PHLDA3 suppress AKT activity to induce NET. IntroductionWalied Abdelghani Kamel Ahmed2023. 4 ～ 2025. 3Rieko Ohki, Head of Laboratory of Fundamental OncologyNational Cancer Center Research Institute― 239 ―Neuroendocrine tumors (NETs) are a relatively rare and heterogeneous tumor type. Neuroendocrine cells are distributed throughout the entire body, and NETs have been found in lung, pancreatic islet, pituitary, thyroid gland, parathyroid gland, rectum, and many other neuroendocrine tissues. PHLDA3 is a p53-regulated Akt repressor that suppresses Akt-mediated survival signaling 1). It has also been reported that PHLDA3 functions as a suppressor of pancreatic NETs (PanNETs) 2). The genomic region of the PHLDA3 gene undergoes loss of heterozygosity at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis (Fig. 1) 3). However, the function of PHLDA3 in thyroid neuroendocrine tumors (ThNETs) is still unknown. Thyroid cancer is the most common endocrine malignancy; recent decades have witnessed a steady increase in its incidence 4). MTC are one of the most common NETs of the thyroid, with an incidence of 3%-4%, that arise from parafollicular C cells which secrete a variety of peptides and hormones, including calcitonin, which is used as a tumor marker 5). Total thyroidectomy remains the ideal choice of treatment. Early diagnosis and treatment are fundamental for a 100% cure rate 6).Elucidation of the mechanisms of thyroid neuroendocrine tumors by loss of the tumor suppressor gene PHLDA3 using a genetically engineered mouse model
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