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Involvement of epigenetics and EMT-related miRNA in arsenic-induced neoplastic transformation and their potential clinical use.
- Source :
-
Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2015 Mar; Vol. 8 (3), pp. 208-21. Date of Electronic Publication: 2015 Jan 13. - Publication Year :
- 2015
-
Abstract
- Exposure to toxicants leads to cumulative molecular changes that overtime increase a subject's risk of developing urothelial carcinoma. To assess the impact of arsenic exposure at a time progressive manner, we developed and characterized a cell culture model and tested a panel of miRNAs in urine samples from arsenic-exposed subjects, urothelial carcinoma patients, and controls. To prepare an in vitro model, we chronically exposed an immortalized normal human bladder cell line (HUC1) to arsenic. Growth of the HUC1 cells was increased in a time-dependent manner after arsenic treatment and cellular morphology was changed. In a soft agar assay, colonies were observed only in arsenic-treated cells, and the number of colonies gradually increased with longer periods of treatment. Similarly, invaded cells in an invasion assay were observed only in arsenic-treated cells. Withdrawal of arsenic treatment for 2.5 months did not reverse the tumorigenic properties of arsenic-treated cells. Western blot analysis demonstrated decreased PTEN and increased AKT and mTOR in arsenic-treated HUC1 cells. Levels of miR-200a, miR-200b, and miR-200c were downregulated in arsenic-exposed HUC1 cells by quantitative RT-PCR. Furthermore, in human urine, miR-200c and miR-205 were inversely associated with arsenic exposure (P = 0.005 and 0.009, respectively). Expression of miR-205 discriminated cancer cases from controls with high sensitivity and specificity (AUC = 0.845). Our study suggests that exposure to arsenic rapidly induces a multifaceted dedifferentiation program and miR-205 has potential to be used as a marker of arsenic exposure as well as a maker of early urothelial carcinoma detection.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Blotting, Western
Case-Control Studies
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic chemically induced
Cell Transformation, Neoplastic genetics
Cells, Cultured
Cohort Studies
DNA Methylation
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
Immunoenzyme Techniques
Male
MicroRNAs genetics
Middle Aged
Neoplasm Invasiveness
PTEN Phosphohydrolase genetics
PTEN Phosphohydrolase metabolism
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
TOR Serine-Threonine Kinases genetics
TOR Serine-Threonine Kinases metabolism
Urinary Bladder drug effects
Urinary Bladder metabolism
Urinary Bladder Neoplasms drug therapy
Urinary Bladder Neoplasms genetics
Young Adult
Arsenic adverse effects
Cell Transformation, Neoplastic pathology
Epigenesis, Genetic genetics
Epithelial-Mesenchymal Transition
MicroRNAs analysis
Urinary Bladder pathology
Urinary Bladder Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1940-6215
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer prevention research (Philadelphia, Pa.)
- Publication Type :
- Academic Journal
- Accession number :
- 25586904
- Full Text :
- https://doi.org/10.1158/1940-6207.CAPR-14-0251