Endocrine Oncology Branch
Endocrine Oncology Branch
Ellis R.J.,Endocrine Oncology Branch |
Ellis R.J.,University of Pennsylvania |
Wang Y.,Genetics Branch |
Stevenson H.,Genetics Branch |
And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Context: Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. Objective: The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. Design: This study was a genome-wide methylation analysis of PTC. Setting: The study was conducted at the National Institutes of Health Clinical Center. Patients: PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. Interventions: CpG methylation status was assessed using advanced genome-wide methylation bead chips. Outcome Measures: Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. Results: PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. Conclusion: PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS). Copyright © 2014 by the Endocrine Society.
Boufraqech M.,Endocrine Oncology Branch |
Zhang L.,Endocrine Oncology Branch |
Jain M.,Endocrine Oncology Branch |
Patel D.,Endocrine Oncology Branch |
And 6 more authors.
Endocrine-Related Cancer | Year: 2014
The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis. © 2014 Society for Endocrinology. Published by Bioscientifica Ltd.