Genomic analysis of Pancreatic Neuroendocrine Tumors (PanNETs) has revealed that these tumors often lack mutations in typical cancer-related genes such as the tumor suppressor gene p53. Instead, PanNET tumorigenesis usually involves mutations in specific PanNET-related genes, such as tumor suppressor gene MEN1. Using a PanNET mouse model, human tissues and human cell lines, we studied the cross-talk among MEN1, p53 and Notch signaling pathways and their role in PanNETs. Here, we show that reactivation of the early developmental program of islet cells underlies PanNET tumorigenesis by restoring the proliferative capacity of PanNET cells. We investigated the role of INSM1, a transcriptional regulator of islet cells’ development, and revealed that its expression and subcellular localization is regulated by MEN1 and p53. Both human and mouse data show that loss of MEN1 in a p53 wild-type genetic background results in increased nuclear INSM1 expression and cell proliferation. Additionally, inhibition of Notch signaling in a p53 wild-type background reduces the proliferation of PanNET cells, due to repression of INSM1 transcription and nuclear localization. Our study elucidates the molecular mechanisms governing the interactions of INSM1 with MEN1, p53 and Notch and their roles in PanNET tumorigenesis, suggesting INSM1 as a key transcriptional regulator of PanNET cell proliferation.

胰腺神经内分泌肿瘤 (PanNETs) 的基因组分析表明，这些肿瘤通常缺乏典型的癌症相关基因如肿瘤抑制基因p53的突变。相反，PanNET 肿瘤发生通常涉及特定 PanNET 相关基因的突变，例如肿瘤抑制基因MEN1。使用 PanNET 小鼠模型、人体组织和人体细胞系，我们研究了MEN1、p53之间的串扰和 Notch 信号通路及其在 PanNETs 中的作用。在这里，我们通过恢复 PanNET 细胞的增殖能力，表明胰岛细胞早期发育程序的重新激活是 PanNET 肿瘤发生的基础。我们研究了 INSM1（一种胰岛细胞发育的转录调节因子）的作用，并发现其表达和亚细胞定位受MEN1和p53的调节。人和小鼠的数据都表明，在p53野生型遗传背景中缺失MEN1会导致核 INSM1 表达和细胞增殖增加。此外，抑制p53中的 Notch 信号由于 INSM1 转录和核定位的抑制，野生型背景降低了 PanNET 细胞的增殖。我们的研究阐明了控制 INSM1 与 MEN1、p53 和 Notch 相互作用的分子机制及其在 PanNET 肿瘤发生中的作用，表明 INSM1 是 PanNET 细胞增殖的关键转录调节因子。