a Department of Radiation Oncology , Stanford University School of Medicine , Stanford , CA , USA.
b Stanford Cancer Institute , Stanford University School of Medicine , Stanford , CA , USA.
Cell Cycle. 2018;17(13):1527-1535. doi: 10.1080/15384101.2018.1464835. Epub 2018 Jul 31.
Although the p53 transcription factor has a well-established role in tumor suppression, little is known about how the non-coding targets of p53 mediate its tumor suppression function. Analysis of ncRNAs regulated by p53 revealed Neat1 as a direct p53 target gene. Neat1 has physiological roles in the development and differentiation of the mammary gland and corpus luteum, but its roles in cancer have been conflicting. To unequivocally understand Neat1 function in cancer, we used Neat1 null mice. Interestingly, we found that Neat1 deficiency promotes transformation both in oncogene-expressing fibroblasts and in a mouse model for pancreatic cancer. Specifically, Neat1 loss in the pancreas results in the enhanced development of preneoplastic lesions associated with dampened expression of differentiation genes. While the exact mechanisms underlying tumor suppression are unknown, there are several described mechanisms that may be responsible for Neat1-mediated tumor suppression. Collectively, these findings suggest that Neat1 enforces differentiation to suppress pancreatic cancer.
尽管 p53 转录因子在肿瘤抑制中具有明确的作用，但对于 p53 的非编码靶标如何介导其肿瘤抑制功能知之甚少。对 p53 调控的 ncRNAs 的分析显示 Neat1 是 p53 的直接靶基因。Neat1 在乳腺和黄体的发育和分化中具有生理作用，但它在癌症中的作用存在矛盾。为了明确了解 Neat1 在癌症中的功能，我们使用了 Neat1 缺失小鼠。有趣的是，我们发现 Neat1 缺乏不仅促进了表达致癌基因的成纤维细胞的转化，也促进了胰腺癌小鼠模型的转化。具体而言，胰腺中 Neat1 的缺失导致与分化基因表达减弱相关的癌前病变的发展增强。虽然肿瘤抑制的确切机制尚不清楚，但有几种描述的机制可能负责 Neat1 介导的肿瘤抑制。总之，这些发现表明 Neat1 通过促进分化来抑制胰腺癌。
