title: The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer.
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, 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.
  
  
  CONCLUSIONS
  Intestinal tumorigenesis may be prevented by oral GUCY2C hormone replacement therapy.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chantell
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Snook
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chengbao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Girondo
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania. scott.waldman@jefferson.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000367:Age Factors; D000368:Aged; D003106:Colon / Q000737:chemistry; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D005768:Gastrointestinal Hormones / Q000032:analysis* / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000032:analysis* / Q000235:genetics*; D019899:Paracrine Communication; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D012007:Rectum / Q000737:chemistry
chemical_list: D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D018000:Receptors, Peptide; C072685:guanylin; C000613654:GUCY2C protein, human; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled