ï¿½ 2015 The Authors. Background & Aims: Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of the corticotropin-releasing-hormone (CRH) family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic epithelial-to-mesenchymal transition (EMT). Methods: The mRNA expression of CRH-family members was analyzed in CRC (n = 56) and control (n = 46) samples, seven CRC cell lines, and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and five normal tissues. Cell proliferation, migration, and invasion were compared between urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in the absence or presence of interleukin-6 (IL-6). CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models. Results: CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared with controls and NCM460 cells, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion, and colony formation in CRC-CRHR2+ cells. In vivo, SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers, and elevated levels of EMT-suppressors. IL-1b, IL-6, and IL-6R mRNAs were diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration, and expression of downstream targets acting as cell cycle- and EMT-inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL-6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival. Conclusions: CRHR2 down-regulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2low CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.