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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 Cancer+Epidemiol+Biomarkers+Prev
2014 ; 23
(11
): 2328-37
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The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally
lost in colorectal cancer
#MMPMID25304930
Wilson C
; Lin JE
; Li P
; Snook AE
; Gong J
; Sato T
; Liu C
; Girondo MA
; Rui H
; Hyslop T
; Waldman SA
Cancer Epidemiol Biomarkers Prev
2014[Nov]; 23
(11
): 2328-37
PMID25304930
show ga
BACKGROUND: Although colorectal cancer is a disease characterized by sequential
accumulation of mutations in epithelial cells, mechanisms leading to genomic
vulnerability contributing to tumor initiation remain undefined. GUCY2C has
emerged as an intestine-specific tumor suppressor controlling epithelial
homeostasis through circuits canonically disrupted in cancer. Surprisingly, the
GUCY2C tumor suppressor is universally overexpressed by human colorectal cancer
cells. This apparent paradox likely reflects silencing of GUCY2C through loss of
its paracrine hormone guanylin. Here, we quantified expression of guanylin mRNA
and protein in tumors and normal epithelia from patients with colorectal cancer.
METHODS: Guanylin mRNA was quantified in tumors and normal adjacent epithelia
from 281 patients by the reverse transcriptase-polymerase chain reaction.
Separately, the guanylin protein was quantified by immunohistochemistry in 54
colorectal tumors and 30 specimens of normal intestinal epithelium. RESULTS:
Guanylin mRNA in colorectum varied more than a 100-fold across the population.
Guanylin mRNA was reduced 100- to 1,000-fold in >85% of tumors compared with
matched normal adjacent mucosa (P < 0.001). Loss of guanylin mRNA was greatest in
tumors from patients <50 years old (P < 0.005) and with the highest expression in
normal adjacent mucosa (Spearman correlation coefficient = 0.61; P < 0.001). In a
separate validation cohort, guanylin protein was detected in all 30 normal
colorectal mucosa specimens, but in none of 54 colorectal tumors. CONCLUSIONS:
Colorectal cancer may initiate as a disease of paracrine hormone insufficiency
through loss of guanylin expression, silencing the GUCY2C tumor suppressor and
disrupting homeostatic mechanisms regulating colorectal epithelia cells. IMPACT:
Intestinal tumorigenesis may be prevented by oral GUCY2C hormone replacement
therapy.