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.

中文翻译：

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去甲肾上腺素-CREB1-miR-373轴促进结肠癌的进展。

肾上腺素系统有助于应激诱发癌症的发作和发展。肾上腺素能纤维是去甲肾上腺素（NE）的主要来源。与NE诱导的结肠癌有关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控网络。我们证明，NE诱导的cAMP反应元件结合蛋白1（CREB1）磷酸化促进增殖，迁移和侵袭人类结肠癌细胞。NE的下游效应子CREB1与miR-373的启动子结合并转录激活其表达。已证明，miR-373表达对于NE诱导的细胞增殖，侵袭和肿瘤生长是必需的。我们证实，miR-373可通过靶向肿瘤抑制物TIMP2和APC来调节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轴来促进结肠癌细胞的增殖和转移。对这种新型信号转导轴的研究可能会为结肠癌的神经调节提供机制上的见解，并有助于设计未来大肠癌应激生物学的临床研究。