Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
Int J Mol Sci. 2020 Jun 8;21(11):4098. doi: 10.3390/ijms21114098.
is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes. We identified as a p53 target gene and found that its protein product is a suppressor of pancreatic neuroendocrine tumors (PanNETs) and a repressor of Akt function. is frequently inactivated by loss of heterozygosity (LOH) and methylation in human PanNETs, and LOH at the gene locus correlates with PanNET progression and poor prognosis. In addition, in -deficient mice, pancreatic islet cells proliferate abnormally and acquire resistance to apoptosis. In this article, we briefly review the roles of p53 and Akt in human neuroendocrine tumors (NETs) and describe the relationship between the p53-PHLDA3 and Akt pathways. We also discuss the role of PHLDA3 as a tumor suppressor in various NETs and speculate on the possibility that loss of PHLDA3 function may be a useful prognostic marker for NET patients indicating particular drug therapies. These results suggest that targeting the downstream PHLDA3-Akt pathway might provide new therapies to treat NETs.
是一种众所周知的肿瘤抑制基因，也是癌症研究中研究最广泛的基因之一。p53 主要作为转录因子发挥作用，可以通过诱导其靶基因来触发多种抗增殖程序。我们鉴定为 p53 靶基因，并发现其蛋白产物是胰腺神经内分泌肿瘤（PanNETs）的抑制剂和 Akt 功能的抑制剂。在人类 PanNETs 中，经常通过杂合性丢失（LOH）和甲基化失活，并且基因座处的 LOH 与 PanNET 进展和预后不良相关。此外，在缺乏的小鼠中，胰岛细胞异常增殖并获得抗凋亡能力。在本文中，我们简要回顾了 p53 和 Akt 在人类神经内分泌肿瘤（NETs）中的作用，并描述了 p53-PHLDA3 和 Akt 途径之间的关系。我们还讨论了 PHLDA3 作为各种 NETs 中的肿瘤抑制因子的作用，并推测 PHLDA3 功能丧失可能是 NET 患者的有用预后标志物，表明特定的药物治疗。这些结果表明，靶向下游 PHLDA3-Akt 途径可能为治疗 NETs 提供新的治疗方法。
