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Disease-Related Expression of the IL-6 / STAT3 / SOCS3 Signaling 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. Janneke van der Woude1
  1. 1 Department of Gastroenterology and Hepatology,Erasmus University Medical Center, Netherlands;
  2. 2 Department of Geriatric, Zhongnan Hospital, Wuhan, China;
  3. 3 Department of Gastroenterology, Internal Medicine, Zhongnan Hospital, Wuhan, China
  1. Correspondence to: Yi Li, Gastroenterology and Hepatology, Erasmus Medical Center, 's Gravendijkwal 230, Rotterdam, 3015 CE, Netherlands; y.li{at}erasmusmc.nl

Abstract

Background/Aims: Mouse models showed that IL-6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of STAT3. We investigated the expression of IL-6 / p-STAT3 / SOCS3 in biopsies from patients with ulcerative colitis (UC) and UC related-colorectal cancer (CRC) progression.

Methods: Biopsies 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. Biopsies (n=9) from patients without colonic abnormalities served as control. The protein expression of IL-6, p-STAT3 and SOCS3 was determined immunohistochemically.

Results: Patients with active UC had significantly more IL-6 and p-STAT3 positive epithelial cells than both inactive UC patients and controls (strong positive IL-6: 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 IL-6 and p-STAT3 compared with controls (strong positive IL-6: 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 biopsies.

Conclusion: We demonstrated the importance of IL-6/p-STAT3 in patients with inflammation induced CRC. Moreover, SOCS3 may be involved UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.

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