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Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis


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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