PloS one, 2015-12, Vol.10 (12), p.e0145198-e0145198
2015
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis
- Ist Teil von
- PloS one, 2015-12, Vol.10 (12), p.e0145198-e0145198
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Chlamydia trachomatis genital infection in women causes serious adverse reproductive complications, and is a strong co-factor for human papilloma virus (HPV)-associated cervical epithelial carcinoma. We tested the hypothesis that Chlamydia induces epithelial-mesenchyme transition (EMT) involving T cell-derived TNF-alpha signaling, caspase activation, cleavage inactivation of dicer and dysregulation of micro-RNA (miRNA) in the reproductive epithelium; the pathologic process of EMT causes fibrosis and fertility-related epithelial dysfunction, and also provides the co-factor function for HPV-related cervical epithelial carcinoma. Using a combination of microarrays, immunohistochemistry and proteomics, we showed that chlamydia altered the expression of crucial miRNAs that control EMT, fibrosis and tumorigenesis; specifically, miR-15a, miR-29b, miR-382 and MiR-429 that maintain epithelial integrity were down-regulated, while miR-9, mi-R-19a, miR-22 and miR-205 that promote EMT, fibrosis and tumorigenesis were up-regulated. Chlamydia induced EMT in vitro and in vivo, marked by the suppression of normal epithelial cell markers especially E-cadherin but up-regulation of mesenchymal markers of pathological EMT, including T-cadherin, MMP9, and fibronectin. Also, Chlamydia upregulated pro-EMT regulators, including the zinc finger E-box binding homeobox protein, ZEB1, Snail1/2, and thrombospondin1 (Thbs1), but down-regulated anti-EMT and fertility promoting proteins (i.e., the major gap junction protein connexin 43 (Cx43), Mets1, Add1Scarb1 and MARCKSL1). T cell-derived TNF-alpha signaling was required for chlamydial-induced infertility and caspase inhibitors prevented both infertility and EMT. Thus, chlamydial-induced T cell-derived TNF-alpha activated caspases that inactivated dicer, causing alteration in the expression of reproductive epithelial miRNAs and induction of EMT. EMT causes epithelial malfunction, fibrosis, infertility, and the enhancement of tumorigenesis of HPV oncogene-transformed epithelial cells. These findings provide a novel understanding of the molecular pathogenesis of chlamydia-associated diseases, which may guide a rational prevention strategy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0145198Titel-ID: cdi_plos_journals_1749961629
- Format
- –
- Schlagworte
- Animals, Bacteria, Cadherins - genetics, Cadherins - metabolism, Caspase inhibitors, Caspases - metabolism, Cell activation, Cervix, Chlamydia, Chlamydia Infections - metabolism, Chlamydia Infections - pathology, Chlamydia trachomatis, Complications, Complications and side effects, Connexin 43, Deactivation, Development and progression, Disease control, Ductile-brittle transition, E-cadherin, Epithelial cells, Epithelial-Mesenchymal Transition, Epithelium, Female, Fertility, Fibronectin, Fibronectins - genetics, Fibronectins - metabolism, Fibrosis, Fracture mechanics, Gelatinase B, HeLa Cells, Homeobox, Homeodomain Proteins - genetics, Homeodomain Proteins - metabolism, Human papillomavirus, Humans, Immunohistochemistry, Inactivation, Infertility, Kruppel-Like Transcription Factors - genetics, Kruppel-Like Transcription Factors - metabolism, Lymphocytes T, Markers, Matrix Metalloproteinase 9 - genetics, Matrix Metalloproteinase 9 - metabolism, Mesenchyme, Mice, Mice, Inbred C57BL, MicroRNAs - genetics, miRNA, Papillomavirus infections, Pathogenesis, Patient outcomes, Protein binding, Proteins, Proteomics, Regulators, Ribonucleic acid, Risk factors, RNA, Rodents, Sexually transmitted diseases, Signaling, Snail Family Transcription Factors, STD, T-cadherin, Thrombospondin 1 - genetics, Thrombospondin 1 - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism, Tumor necrosis factor, Tumor Necrosis Factor-alpha - metabolism, Tumor necrosis factor-α, Tumorigenesis, Viruses, Zinc, Zinc Finger E-box-Binding Homeobox 1, Zinc finger proteins