4.5 Article

Overexpression of Cancer-Associated Stem Cell Gene OLFM4 in the Colonic Epithelium of Patients With Primary Sclerosing Cholangitis

期刊

INFLAMMATORY BOWEL DISEASES
卷 27, 期 8, 页码 1316-1327

出版社

OXFORD UNIV PRESS INC
DOI: 10.1093/ibd/izab025

关键词

primary sclerosing cholangitis; inflammatory bowel disease; organoids; epithelium

资金

  1. Wellcome Trust [101734/Z/13/Z, 212240/Z/18/Z]
  2. National Institute for Health Research Research Capability Fund
  3. National Institute for Health Research Oxford Biomedical Research Centre (Gastroenterology and Mucosal Immunity Theme)
  4. Versus Arthritis
  5. Wellcome Trust [212240/Z/18/Z, 101734/Z/13/Z] Funding Source: Wellcome Trust

向作者/读者索取更多资源

Higher expression of OLFM4, a cancer stemness gene induced by IL-22, is present in PSC-UC, suggesting that IL-22 responses may result in alterations of the intestinal stem-cell niche in these patients. IFN gamma stimulation resulted in the downregulation of LGR5 in EpOCs, whereas higher expression of OLFM4 was observed after IL-22 stimulation, indicating a complex interplay between these cytokines in contributing to carcinogenesis in PSC-UC.
Background: To examine immune-epithelial interactions and their impact on epithelial transformation in primary sclerosing cholangitis-associated ulcerative colitis (PSC-UC) using patient-derived colonic epithelial organoid cultures (EpOCs). Methods: The EpOCs were originated from colonic biopsies from patients with PSC-UC (n = 12), patients with UC (n = 14), and control patients (n = 10) and stimulated with cytokines previously associated with intestinal inflammation (interferon (IFN) gamma and interleukin (IL)-22). Markers of cytokine downstream pathways, stemness, and pluripotency were analyzed by real-time quantitative polymerase chain reaction and immunofluorescence. The OLFM4 expression in situ was assessed by RNAscope and immunohistochemistry. Results: A distinct expression of stem cell-associated genes was observed in EpOCs derived from patients with PSC-UC, with lower expression of the classical stem-cell marker LGR5 and overexpression of OLFM4, previously associated with pluripotency and early stages of neoplastic transformation in the gastrointestinal and biliary tracts. High levels of OLFM4 were also found ex vivo in colonic biopsies from patients with PSC-UC. In addition, IFN gamma stimulation resulted in the downregulation of LGR5 in EpOCs, whereas higher expression of OLFM4 was observed after IL-22 stimulation. Interestingly, expression of the IL-22 receptor, IL22RA1, was induced by IFN gamma, suggesting that a complex interplay between these cytokines may contribute to carcinogenesis in PSC-UC. Conclusions: Higher expression of OLFM4, a cancer stemness gene induced by IL-22, is present in PSC-UC, suggesting that IL-22 responses may result in alterations of the intestinal stem-cell niche in these patients.

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