Abstract
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.
Highlights
Organisms continuously encounter a variety of stresses that cause maladaptation and may even result in cancer
In this study, using loss-/gain-of-function, ChIP, and luciferase reporter assays, we reveal the importance of the NE–cyclic AMP (cAMP) response element-binding protein 1 (CREB1)–miR-373 axis and the oncogenic role of miR-373 in colon cancer
We have demonstrated that NE promotes the progression of colon cancer via CREB1 activity-dependent transcription, enhancing the expression of oncogenic miR-373 and reducing the expression of the miR-373 targets adenomatous polyposis coli (APC) and tissue inhibitor of metalloproteinases 2 (TIMP2)
Summary
Organisms continuously encounter a variety of stresses that cause maladaptation and may even result in cancer. Increasing evidence indicates the importance of stress in cancer progression. Stress mediators such as neuroendocrine hormones enhance cancer pathogenesis by inhibiting antitumor immune responses; recent studies suggest that the peripheral nerves in tumor-nervous connections (TNCs) modulate the physiological behavior of cancer cells and affect cancer progression (Amit et al, 2016; Chida et al, 2008; Faulkner et al, 2019; Jobling et al, 2015; Mauffrey et al, 2019; Quaegebeur et al, 2011; Reiche et al, 2004; Thaker et al, 2006). Activation of the adrenergic system significantly affects stress-induced cancer progression (Magnon et al, 2013). It is known that physiological changes are induced by the adrenergic system, the cellular targets and molecular mechanisms involved in the neural regulation of CRC remain to be investigated; the results of such studies may provide a basis for novel therapeutic interventions (Coelho et al, 2017)
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