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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Cell+Mol+Gastroenterol+Hepatol
2015 ; 1
(6
): 610-630
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Diminished expression of CRHR2 in human colon cancer promotes tumor growth and
EMT via persistent IL-6/Stat3 signaling
#MMPMID26495412
Rodriguez JA
; Huerta-Yepez S
; Law IK
; Baay-Guzman GJ
; Tirado-Rodriguez B
; Hoffman JM
; Iliopoulos D
; Hommes DW
; Verspaget HW
; Chang L
; Pothoulakis C
; Baritaki S
Cell Mol Gastroenterol Hepatol
2015[Nov]; 1
(6
): 610-630
PMID26495412
show ga
BACKGROUND & AIMS: Chronic inflammation promotes development and progression of
colorectal cancer (CRC). We explored the distribution of
Corticotropin-Releasing-Hormone (CRH)-family of receptors and ligands in CRC and
their contribution in tumor growth and oncogenic EMT. METHODS: mRNA expression of
CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC
cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was
performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and
invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and
CRHR2-overexpressing (CRHR2+) cells in absence or presence of 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 to controls and NCM460,
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 where 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 downregulation 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.