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Genotoxicity of cytolethal distending toxin (cdt) on isogenic human colorectal cell lines: potential promoting effects for colorectal carcinogenesis
- Source :
- Frontiers in Cellular and Infection Microbiology, Frontiers in Cellular and Infection Microbiology, Frontiers, 2016, 6, pp.1-13. ⟨10.3389/fcimb.2016.00034⟩, Frontiers in Cellular and Infection Microbiology, Vol 6 (2016), Frontiers in Cellular and Infection Microbiology (6), 1-13. (2016)
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
Abstract
- International audience; The composition of the human microbiota influences tumorigenesis, notably in colorectal cancer (CRC). Pathogenic Escherichlacoli possesses a variety of virulent factors, among them the Cytolethal Distending Toxin (CDT). CDT displays dual DNase and phosphatase activities and induces DNA double strand breaks, cell cycle arrest and apoptosis in a broad range of mammalian cells. As CDT could promote malignant transformation, we investigated the cellular outcomes induced by acute and chronic exposures to E. coli CDT in normal human colon epithelial cells (HCECs). Moreover, we conducted a comparative study between isogenic derivatives cell lines of the normal HCECs in order to mimic the mutation of three major genes found in CRC genetic models: APC, KRAS, and TP53. Our results demonstrate that APC and p53 deficient cells showed impaired DNA damage response after CDT exposure, whereas HCECs expressing oncogenic KRAS(V12) were more resistant to CDT. Compared to normal HCECs, the precancerous derivatives exhibit hallmarks of malignant transformation after a chronic exposure to CDT. HCECs defective in APC and p53 showed enhanced anchorage independent growth and genetic instability, assessed by the micronucleus formation assay. In contrast, the ability to grow independently of anchorage was not impacted by CDT chronic exposure in KRAS(V12) HCECs, but micronucleus formation is dramatically increased. Thus, CDT does not initiate CRC by itself, but may have promoting effects in premalignant HCECs, involving different mechanisms in function of the genetic alterations associated to CRC.
- Subjects :
- 0301 basic medicine
p53
DNA Repair
Cytolethal distending toxin
Carcinogenesis
[SDV]Life Sciences [q-bio]
lcsh:QR1-502
Apoptosis
medicine.disease_cause
lcsh:Microbiology
Malignant transformation
Intestinal mucosa
DNA Breaks, Double-Stranded
Intestinal Mucosa
Original Research
DNA double strand breaks
3. Good health
Infectious Diseases
KRAS
Colorectal Neoplasms
Microbiology (medical)
DNA repair
DNA damage
Adenomatous Polyposis Coli Protein
Bacterial Toxins
Immunology
colorectal cancer
Biology
Microbiology
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Cell Line, Tumor
Genetic model
Escherichia coli
medicine
Humans
cytolethal distending toxin
APC
genotoxicity
Epithelial Cells
Cell Cycle Checkpoints
030104 developmental biology
Carcinogens
Cancer research
sense organs
Tumor Suppressor Protein p53
Subjects
Details
- Language :
- English
- ISSN :
- 22352988
- Database :
- OpenAIRE
- Journal :
- Frontiers in Cellular and Infection Microbiology, Frontiers in Cellular and Infection Microbiology, Frontiers, 2016, 6, pp.1-13. ⟨10.3389/fcimb.2016.00034⟩, Frontiers in Cellular and Infection Microbiology, Vol 6 (2016), Frontiers in Cellular and Infection Microbiology (6), 1-13. (2016)
- Accession number :
- edsair.doi.dedup.....6e0dbf7f663ddef0d04e330e08b8f7c2