Xu Eugenia Y, Vosburgh Evan, Wong Chung, Tang Laura H, Notterman Daniel A
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Oncotarget. 2020 Jul 14;11(28):2718-2739. doi: 10.18632/oncotarget.27660.
Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs , , and have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of singly led to prolactinomas in female mice, and deletion of alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.
抑癌基因（TSGs）的遗传改变常常被观察到具有累积性或协同性致瘤作用。我们研究了TSGs 、 、 和 在抑制小鼠神经内分泌肿瘤（NETs）方面是否具有协同作用。我们使用Cre-LoxP系统在表达胰岛素II基因的细胞中对这四个基因进行了成对纯合缺失。通过监测这些小鼠垂体（Pit）和胰腺（Pan）的生长并检查其组织病理学，我们证明pRB在抑制垂体神经内分泌肿瘤（PitNETs）方面与PTEN具有最强的协同功能，在抑制PitNETs和胰腺神经内分泌肿瘤（PanNETs）方面分别与Menin和TRP53具有很强的协同功能。TRP53在抑制垂体病变方面与PTEN具有较弱的协同功能。我们还发现单独缺失 会导致雌性小鼠患催乳素瘤，而单独缺失 会导致胰腺胰岛增生。总体而言，我们的数据表明pRB和PTEN途径在抑制PitNETs中起重要作用，而Menin介导的途径在抑制PanNETs中起重要作用。了解这些基因和途径对NETs的分子机制将有助于我们理解神经内分泌肿瘤发生的分子机制，并开发有效的NET治疗临床前小鼠模型以改善人类临床结果。
