Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China.
School of Basic Medical Science, Xi'an Medical University, China.
Mol Oncol. 2020 May;14(5):1059-1073. doi: 10.1002/1878-0261.12657. Epub 2020 Mar 13.
The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.
肾上腺素能系统有助于应激诱导的癌症发生和进展。肾上腺素能纤维是去甲肾上腺素（NE）的主要来源。NE 诱导结肠癌的潜在机制仍有待了解。在这项研究中，我们描述了 NE 在结肠癌进展中的功能和调节网络。我们证明，NE 诱导的 cAMP 反应元件结合蛋白 1（CREB1）磷酸化促进人结肠癌细胞的增殖、迁移和侵袭。NE 的下游效应物 CREB1 与 miR-373 的启动子结合，并转录激活其表达。miR-373 的表达对于 NE 诱导的细胞增殖、侵袭和肿瘤生长是必需的。我们通过靶向肿瘤抑制因子 TIMP2 和 APC 证实，miR-373 可调节体外和体内结肠癌细胞的增殖和侵袭。我们的数据表明，NE 通过激活 CREB1-miR-373 轴促进结肠癌细胞的增殖和转移。对这条新信号轴的研究可能为神经对结肠癌的调控提供机制上的见解，并有助于未来在结直肠癌应激生物学方面的临床研究。
