Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6622-6629. doi: 10.1073/pnas.1920017117. Epub 2020 Mar 10.
A more comprehensive understanding of the molecular mechanisms underlying pancreatic diseases, including pancreatitis and cancer, is essential to improve clinical management. MEN1 has established roles in epigenetic regulation and tumor suppression in the endocrine pancreas; however, intriguing recent data suggest MEN1 may also function in the exocrine pancreas. Using physiologically relevant genetic mouse models, we provide direct evidence that Men1 is essential for exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Men1 loss causes increased injury and impaired regeneration following acute caerulein-induced pancreatitis, leading to more severe damage, loss of the normal acinar compartment, and increased cytokeratin 19-positive metaplasias and immune cell infiltration. We further demonstrate the Men1 protein is stabilized in response to insult, and loss of Men1 is associated with the overexpression of proinflammatory Jund target genes, suggesting that loss of Men1-mediated repression of Jund activity is, at least in part, responsible for the impaired response. Finally, we demonstrate that loss significantly accelerates mutant Kras-dependent oncogenesis. Combined, this work establishes Men1 as an important mediator of pancreas homeostasis in vivo.
更全面地了解胰腺疾病（包括胰腺炎和癌症）的分子机制对于改善临床管理至关重要。MEN1 在内分泌胰腺的表观遗传调控和肿瘤抑制中发挥着重要作用；然而，最近引人注目的数据表明 MEN1 也可能在外分泌胰腺中发挥作用。我们使用生理相关的遗传小鼠模型，提供了直接证据表明 Men1 对于炎症和致癌应激下的外分泌胰腺稳态是必需的。Men1 缺失导致急性雨蛙肽诱导的胰腺炎后损伤增加和再生受损，导致更严重的损伤、正常腺泡区的丧失以及细胞角蛋白 19 阳性化生和免疫细胞浸润增加。我们进一步证明 Men1 蛋白在受到损伤时会稳定下来，并且 Men1 的缺失与促炎 Jund 靶基因的过度表达相关，这表明至少部分原因是 Men1 介导的 Jund 活性抑制的丧失导致了反应受损。最后，我们证明缺失显著加速了突变 Kras 依赖性肿瘤发生。综上所述，这项工作确立了 Men1 作为体内胰腺稳态的重要调节剂。
