title: Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis.
abstract: BACKGROUND
  Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of transcription 3 (STAT3).
  
  
  OBJECTIVE
  To investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.
  
  
  METHODS
  Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.
  
  
  RESULTS
  Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p<or=0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.
  
  
  CONCLUSIONS
  The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, Netherlands. y.li@erasmusmc.nl
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Colin
authors.initials: C
authors.lastname: de Haar
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Jasper
authors.initials: J
authors.lastname: Deuring
authors.forename: Monique M
authors.initials: MM
authors.lastname: Gerrits
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
mesh_terms: D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000150:complications / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins