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The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer.

Publication ,  Journal Article
Wilson, C; Lin, JE; Li, P; Snook, AE; Gong, J; Sato, T; Liu, C; Girondo, MA; Rui, H; Hyslop, T; Waldman, SA
Published in: Cancer Epidemiol Biomarkers Prev
November 2014

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.

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Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

November 2014

Volume

23

Issue

11

Start / End Page

2328 / 2337

Location

United States

Related Subject Headings

  • Rectum
  • Receptors, Peptide
  • Receptors, Guanylate Cyclase-Coupled
  • Receptors, Enterotoxin
  • RNA, Messenger
  • Prospective Studies
  • Paracrine Communication
  • Natriuretic Peptides
  • Middle Aged
  • Male
 

Citation

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Wilson, C., Lin, J. E., Li, P., Snook, A. E., Gong, J., Sato, T., … Waldman, S. A. (2014). The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev, 23(11), 2328–2337. https://doi.org/10.1158/1055-9965.EPI-14-0440
Wilson, Chantell, Jieru E. Lin, Peng Li, Adam E. Snook, Jianping Gong, Takahiro Sato, Chengbao Liu, et al. “The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer.Cancer Epidemiol Biomarkers Prev 23, no. 11 (November 2014): 2328–37. https://doi.org/10.1158/1055-9965.EPI-14-0440.
Wilson C, Lin JE, Li P, Snook AE, Gong J, Sato T, et al. The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2328–37.
Wilson, Chantell, et al. “The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer.Cancer Epidemiol Biomarkers Prev, vol. 23, no. 11, Nov. 2014, pp. 2328–37. Pubmed, doi:10.1158/1055-9965.EPI-14-0440.
Wilson C, Lin JE, Li P, Snook AE, Gong J, Sato T, Liu C, Girondo MA, Rui H, Hyslop T, Waldman SA. The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2328–2337.

Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

November 2014

Volume

23

Issue

11

Start / End Page

2328 / 2337

Location

United States

Related Subject Headings

  • Rectum
  • Receptors, Peptide
  • Receptors, Guanylate Cyclase-Coupled
  • Receptors, Enterotoxin
  • RNA, Messenger
  • Prospective Studies
  • Paracrine Communication
  • Natriuretic Peptides
  • Middle Aged
  • Male