Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

Dongsheng Zhang; Wenjuan Tang; Haitao Niu; William Tse; Hai-Bin Ruan; Helmut Dolznig; Thomas Knösel; Friedrich Karl-Heinz; Madeleine Themanns; Jiang Wang; Mingquan Song; Lee Denson; Lukas Kenner; Richard Moriggl; Yi Zheng; Xiaonan Han

doi:10.1016/j.gendis.2022.11.024

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Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

Full-length article | 更新时间：2024-02-04

- Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia
- Genes & Diseases Vol. 1, Issue 1, Pages: 413-429(2024)
- 作者机构：
  
  1. Division of Hematology and Oncology, Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU), School of Medicine,OH,Cleveland,USA,44109
  2. Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU),OH,Cleveland,USA,44106
  3. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC),OH,Cincinnati,USA,45229
  4. Children's Hospital of Fudan University,Shanghai,China,201102
  5. School of Medicine, Jinan University,Guangdong,Guangzhou,China,510632
  6. Laboratory Animal Science (ILAS), Chinese Academy of Medical Science (CAMS) and Peking Union Medical College (PUMC),Beijing,China,100006
  7. Department of Integrative Biology and Physiology, University of Minnesota Medical School,MI,Minneapolis,USA,55455
  8. Institute of Medical Genetics, Medical University of Vienna,Vienna,Austria,1040
  9. Institute of Pathology, Ludwig-Maximilians-University Munich,Munich,Germany,80539
  10. Institute of Biochemistry II, University Hospital Jena, Jena,Germany,07743
  11. Laboratory Animal Pathology, University of Veterinary Medicine Vienna,Vienna,Austria,1210
  12. Department of Pathology, University of Cincinnati,OH,Cincinnati,USA,45221
  13. Department of Gastroenterology, The Affiliated Hospital of Qingdao University,Shandong,Qingdao,China,266005
  14. Department of Pathology, Medical University of Vienna,Vienna,Austria,1040
  15. Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria,1090
  16. Medical University of Vienna,Vienna,Austria,1040
  17. Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna,Vienna,Austria,1210
  18. Division of Experimental Hematology, CCHMC,OH,Cincinnati,USA,45229
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.11.024
  CLC：
- Published：2024，
  
  Published Online：1 January 2024，
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Dongsheng Zhang, Wenjuan Tang, Haitao Niu, et al. Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia. [J]. Genes & Diseases 1(1):413-429(2024)
DOI：

Dongsheng Zhang, Wenjuan Tang, Haitao Niu, et al. Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia. [J]. Genes & Diseases 1(1):413-429(2024) DOI： 10.1016/j.gendis.2022.11.024.

摘要

Abstract

CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD)

colorectal cancer

aging

and IESC injury to determine the loss of intestinal

Cdc42

upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.

Cdc42

floxed mice were crossed with

Villin

-Cre

Villin

-CreER

and/or

Lgr5-

eGFP-IRES-CreER

Bmi1

-CreER

mice to generate

Cdc42

deficient mice. Irradiation

colitis

aging

and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation

IESC/progenitor regenerative capacity

and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast

lower levels of CDC42 were found in the inflamed IBD colon. Colonic

Cdc42

depletion significantly reduced Lgr5

IESCs

increased progenitors' hyperplasia

and induced mucosal inflammation

which led to crypt dysplasia. Colonic

Cdc42

depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of

Cdc42

reduced colonic Lgr5

IESC regeneration. In conclusion

depletion of

Cdc42

reduces the IESC regeneration and IEC repair

leading to prolonged mucosal inflammation. Constitutive monogenic loss of

Cdc42

induces mucosal inflammation

which could result in intestinal neoplasia in the context of aging.

关键词

Keywords

Cell division cycle 42 (CDC42)ColitisColorectal cancer (CRC)Inflammatory bowel diseases (IBD)Intestinal epithelial cell (IEC)Intestinal epithelial stem cell (IESC)Irradiation

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