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Abstract
Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting.
Highlights
Stress, known as a threat to maintaining organism homeostasis, is an event that most animal species experience
In rat TNBS–induced colitis models, a significant decrease in CRH receptor 2 (CRHR2) expression was observed on myenteric neurons and macrophages during the inflammation onset, followed by significant induction of Ucn2 expression, which possibly was mediated by increased infiltration of Ucn2-expressing immune and fibroblast cells [9,94,101]
We showed that mice deficient in corticotropin releasing hormone (CRH) were more susceptible to DSS-induced colitis, possibly due to overproduction of IL-12 and prostaglandin E2, while having significantly decreased toll-like receptor 4 (TLR4) levels before, but not after the colitis induction
Summary
Known as a threat to maintaining organism homeostasis, is an event that most animal species experience. Several studies have clearly shown that stress alters intestinal functions such as gut motor and mucosal activity, visceral hypersensitivity, as well as epithelial barrier and local immune functions, via pathways involving peripheral CRH signaling [16]. These alterations have been reported to be involved in the onset and pathophysiology of chronic intestinal disorders, including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) [9,15,17]. Focus is given on the participation of the central and peripheral CRH system, as the core component of the molecular signaling networks that interconnect the above processes and can be targeted therapeutically
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