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Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling

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...

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Autores principales: Rodriguez, Jorge A., Huerta-Yepez, Sara, Law, Ivy Ka Man, Baay-Guzman, Guillermina J., Tirado-Rodriguez, Belen, Hoffman, Jill M., Iliopoulos, Dimitrios, Hommes, Daniel W., Verspaget, Hein W., Chang, Lin, Pothoulakis, Charalabos, Baritaki, Stavroula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610032/
https://www.ncbi.nlm.nih.gov/pubmed/26495412
http://dx.doi.org/10.1016/j.jcmgh.2015.08.001
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author Rodriguez, Jorge A.
Huerta-Yepez, Sara
Law, Ivy Ka Man
Baay-Guzman, Guillermina J.
Tirado-Rodriguez, Belen
Hoffman, Jill M.
Iliopoulos, Dimitrios
Hommes, Daniel W.
Verspaget, Hein W.
Chang, Lin
Pothoulakis, Charalabos
Baritaki, Stavroula
author_facet Rodriguez, Jorge A.
Huerta-Yepez, Sara
Law, Ivy Ka Man
Baay-Guzman, Guillermina J.
Tirado-Rodriguez, Belen
Hoffman, Jill M.
Iliopoulos, Dimitrios
Hommes, Daniel W.
Verspaget, Hein W.
Chang, Lin
Pothoulakis, Charalabos
Baritaki, Stavroula
author_sort Rodriguez, Jorge A.
collection PubMed
description 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. CRHR2(low) CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.
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spelling pubmed-46100322016-11-01 Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling Rodriguez, Jorge A. Huerta-Yepez, Sara Law, Ivy Ka Man Baay-Guzman, Guillermina J. Tirado-Rodriguez, Belen Hoffman, Jill M. Iliopoulos, Dimitrios Hommes, Daniel W. Verspaget, Hein W. Chang, Lin Pothoulakis, Charalabos Baritaki, Stavroula Cell Mol Gastroenterol Hepatol Original Research 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. CRHR2(low) CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes. Elsevier 2015-08-20 /pmc/articles/PMC4610032/ /pubmed/26495412 http://dx.doi.org/10.1016/j.jcmgh.2015.08.001 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Rodriguez, Jorge A.
Huerta-Yepez, Sara
Law, Ivy Ka Man
Baay-Guzman, Guillermina J.
Tirado-Rodriguez, Belen
Hoffman, Jill M.
Iliopoulos, Dimitrios
Hommes, Daniel W.
Verspaget, Hein W.
Chang, Lin
Pothoulakis, Charalabos
Baritaki, Stavroula
Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title_full Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title_fullStr Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title_full_unstemmed Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title_short Diminished Expression of Corticotropin-Releasing Hormone Receptor 2 in Human Colon Cancer Promotes Tumor Growth and Epithelial-to-Mesenchymal Transition via Persistent Interleukin-6/Stat3 Signaling
title_sort diminished expression of corticotropin-releasing hormone receptor 2 in human colon cancer promotes tumor growth and epithelial-to-mesenchymal transition via persistent interleukin-6/stat3 signaling
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610032/
https://www.ncbi.nlm.nih.gov/pubmed/26495412
http://dx.doi.org/10.1016/j.jcmgh.2015.08.001
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