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Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis
  1. Yi Li1,
  2. Colin de Haar1,
  3. Min Chen2,
  4. Jasper Deuring1,
  5. Monique M Gerrits1,
  6. Ron Smits1,
  7. Bing Xia3,
  8. Ernst J Kuipers1,
  9. C Janneke van der Woude1
  1. 1Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, Netherlands
  2. 2Department of Geriatric, Zhongnan Hospital, Wuhan University, China
  3. 3Department of Gastroenterology, Internal Medicine, Zhongnan Hospital, Wuhan University, China
  1. Correspondence to Yi Li, Department of Gastroenterology and Hepatology, Erasmus MC, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; y.li{at}erasmusmc.nl

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≤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.

Conclusion 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.

  • Ulcerative colitis (UC)
  • colorectal cancer (CRC)
  • interleukin 6 (IL6)
  • signal transducers and activators of transcription 3 (STAT3)
  • the suppressor of cytokine signalling 3 (SOCS3)
  • carcinogenesis
  • cell signalling
  • inflammatory bowel disease
  • intestinal epithelium
  • UC
  • ulcerative colitis
  • CRC
  • colorectal cancer
  • IL6
  • interleukin 6
  • STAT3
  • signal transducers and activators of transcription 3
  • SOCS3
  • suppressor of cytokine signalling 3
  • IBD
  • inflammatory bowel disease
  • LGD
  • low-grade dysplasia
  • HGD
  • high-grade dysplasia
  • JAK
  • Janus kinases
  • sIL6R
  • soluble IL6 receptor
  • p-STAT3
  • phosphorylated STAT3
  • SH2
  • Src homology 2
  • HE
  • haematoxylin & eosin
  • IHC
  • immunohistochemistry
  • DSS
  • dextran sulphate sodium
  • MSP
  • methylation-specific PCR

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Footnotes

  • YL and CdH contributed equally to this paper.

  • Funding State Scholarship Fund, China.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Netherlands ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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