gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis
Open accessAbstract
Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.
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The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.
“The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.12,15,46,48,49”
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 [46]
The Introduction describes STAT3 activation as a feature of many human malignancies, and the Discussion reports a role for gp130/STAT3 signaling in inflammation-associated tumors. However, the paper’s direct evidence concerns a mouse model of colitis-associated cancer; it does not establish the role of the full IL-6/JAK/STAT3 pathway in human colorectal cancer specifically. The supplied copy gives no page numbers for these sections. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIL-6 has been previously identified as a key cytokine that directly induces tumour growth in CRC via STAT3 activation in IECs.
“IL-6 has been previously identified as a key cytokine that directly induces tumuor growth in CRC via STAT3 activation in IECs.12,15,46,47.”
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 [46]
The Summary and Discussion (page numbers unavailable) report that IEC Stat3 activation promotes tumor growth in a mouse model of colitis-associated cancer and that IL-6-dependent Stat3 activation contributes to this process. The paper also identifies IL-11-dependent activation and describes IL-6 and IL-11 as having redundant effects; it does not establish IL-6 alone as the key driver of CRC growth generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIL-6R evokes a myriad of responses, including metabolic actions, through STAT3.
“IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.31,32,33,34”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [31]
The Significance section explains that IL-6 receptor signaling through gp130 engages STAT3, and the Discussion describes effects on cell survival and proliferation. The passages do not describe metabolic actions, so that specific part of the claim is unsupported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIL-6 is a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6-STAT3 pathway.
“IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [20]
The Discussion (page unavailable) reports that IL-6-dependent STAT3 activation promotes colitis-associated cancer, supporting the inflammation-and-cancer portion of the claim. Our copy does not address autoimmunity or establish that IL-6 acts mainly through STAT3 across all three conditions; the Significance section also describes other downstream gp130 pathways. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSTAT3 activation by IL-6 is required for intestinal epithelial cell survival and cell-cycle progression during colitis-induced tumorigenesis.
“STAT3 activation by IL-6 is required for intestinal epithelial cell survival and cell-cycle progression during colitis-induced tumorigenesis (20).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [20]
The Summary (page unavailable) reports that Stat3 mediates IL-6- and IL-11-dependent intestinal epithelial cell survival and promotes cell-cycle progression in a colitis-associated cancer model. But the section “Stat3 Stimulates Regeneration and Proliferation during Colitis” (page unavailable) reports that loss of IL-6 signaling alone did not reduce epithelial proliferation; IL-6 and IL-11 had redundant activity. The paper therefore supports a role for Stat3, but not a requirement for IL-6 specifically. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Gp130Y757F/Y757F mice show enhanced colitis-associated tumorigenesis in a manner dependent on enhanced activation of STAT3.
“Gp130Y757F/Y757F mice show enhanced colitis-associated tumorigenesis in a manner dependent on the enhanced activation of STAT3 (20).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [20]
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- Authors
- Bollrath, J., Phesse, T. J., von Burstin, V. A., Putoczki, T., Bennecke, M., Bateman, T., Nebelsiek, T., Lundgren-May, T., Canli, Ö., Schwitalla, S., Matthews, V., Schmid, R. M., Kirchner, T., Arkan, M. C., Ernst, M., & Greten, F. R.
- Affiliations
- TUM Klinikum (DE)
- The Royal Melbourne Hospital (AU)
- Pathologisches Institut (DE)
- Corresponding author
- Ernst, Matthias
- Greten, Florian R.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 15
- Issue
- 2
- Pages
- 91-102
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2105269215
- Cited by
- 946
- References
- 6
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 27 · 2023: 33 · 2022: 48 · 2021: 48 · 2020: 56 · 2019: 54 · 2018: 62 · 2017: 60 · 2016: 62 · 2015: 77 · 2014: 71 · 2013: 80 · 2012: 75
- FWCI
- 38.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2118 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Wilhelm Sander-Stiftung (2005.146.1)
- Deutsche Forschungsgemeinschaft (106772, Gr1916/2-2, SFB 456)
- Fritz Thyssen Stiftung (10.05.2.168)
- Deutsche Krebshilfe (107977)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- gp130, STAT3, colitis-associated colorectal cancer, enterocytes, cell survival, cell cycle progression, interleukin-6, interleukin-11, chronic inflammation, tumor promotion, mucosal inflammation, intestinal epithelial cells, G1/S transition, G2/M transition
- MeSH terms
- Animals, Cell Cycle, Cell Survival, Colitis, Humans, Inflammation, Intestinal Mucosa, Neoplasms, Regeneration, Signal Transduction, Interleukin-6, Apoptosis, Interleukin-11, Cell Cycle Proteins, Enterocytes, Cell Proliferation, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
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