Journal
PLOS ONE
Volume 15, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0234873
Keywords
-
Categories
Funding
- Hungarian Scientific Research Fund [67925, 100904, 119283]
- Development of the Scientific Workshops of Medical, Health Science and Pharmacist Education predoctoral fellowship [EFOP-3.6.3-VEKOP-16-201700009, HRDOP-3.6.3-CCHOP-16]
- Austrian Science Fund [FWF P 22287-B13]
- European Union Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange Evaluations (RISE) project [645756 GLYCANC]
Ask authors/readers for more resources
Objective Comparison of human mRNA microarray results from tumor-associated and normal cervical fibroblasts revealed significantTFPI2downregulation in tumor-associated fibroblasts isolated from cervical cancer, indicating thatTFPI2downregulation may play an important role in the pathogenesis of the disease. In the present work, we investigated the mechanism ofTFPI2downregulation in tumor-associated fibroblasts and tumor cells. Methods In vitromodels of monocultures and co-cultures were established with tumor cells and fibroblasts to explore the changes of TFPI-2 expression and epigenetic modifications of theTFPI2gene. Results TheTFPI2gene was hypermethylated only in tumor cells. Reduction of TFPI-2 protein levels in tumor-associated fibroblasts, although the gene was not methylated, suggested alternative regulatory mechanisms of gene expression, such as inhibition by microRNAs. The expression pattern ofmiR-23a, a gene thought to inhibitTFPI2translation, showed changes strongly correlated to detected TFPI-2 protein alterations. Transfections withmiR-23amimics resulted in a decrease of TFPI-2 protein expression whereasmiR-23ainhibitors increased the TFPI-2 amount. Due to downregulation ofmiR-23aexpression by HPV in cancer cells,TFPI2was silenced by promoter methylation. In contrary,miR-23awas active in HPV-free fibroblasts and inactivatedTFPI2. Conclusion These results indicate dual epigenetic inhibition ofTFPI2on the transcription level by promoter methylation in cancer cells and on the translation level bymiR-23ain tumor-associated fibroblasts. As a consequence, inactivation of theTFPI2gene plays a strategic role in the progression of cervical cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available