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≤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.
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SOCS3 is a downstream target gene of the IL-6/JAK/STAT3 signalling cascade and inhibits STAT3 activation in CRC.
“One of the downstream target genes of this signalling cascade is the negative feedback regulator suppressor of cytokine signalling 3 [SOCS3] that inhibits STAT3 activation in CRC.50,51”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [51]
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- Authors
- Li, Y., de Haar, C., Chen, M., Deuring, J., Gerrits, M. M., Smits, R., Xia, B., Kuipers, E. J., & van der Woude, C. J.
- Affiliations
- Erasmus MC (NL)
- Wuhan University (CN)
- Corresponding author
- Li, Yi
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2009-11-18
- Volume
- 59
- Issue
- 2
- Pages
- 227-235
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2101229561
- Cited by
- 339
- References
- 3
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 19 · 2023: 15 · 2022: 23 · 2021: 23 · 2020: 18 · 2019: 15 · 2018: 16 · 2017: 14 · 2016: 18 · 2015: 27 · 2014: 25 · 2013: 29 · 2012: 30
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Mayo Clinic
- China Scholarship Council
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- ulcerative colitis, colorectal cancer, STAT3 phosphorylation, SOCS3, interleukin-6, low-grade dysplasia, high-grade dysplasia, inflammation-induced carcinogenesis, colonic epithelium, gene expression, colorectal cancer progression
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Adult, Cell Transformation, Neoplastic, Colitis, Ulcerative, Colon, DNA, Neoplasm, Epithelial Cells, Female, Humans, Immunoenzyme Techniques, Intestinal Mucosa, Male, Middle Aged, Colorectal Neoplasms, Signal Transduction, Interleukin-6, Disease Progression, DNA Methylation, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Young Adult
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