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

Chantell Wilson, Jieru E. Lin, Peng Li, Adam E. Snook, Jianping Gong, Takahiro Sato, Chengbao Liu, Melanie A. Girondo, Hallgeir Rui, Terry Hyslop, Scott A. Waldman

Research output: Contribution to journalArticlepeer-review

Abstract

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,wequantified expression of guanylinmRNAand protein in tumors and normal epithelia from patients with colorectal cancer. Methods: GuanylinmRNAwas 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: GuanylinmRNAin colorectum varied more than a 100-fold across the population. GuanylinmRNA 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.

Original languageEnglish (US)
Pages (from-to)2328-2337
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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