Enhancer of Zeste Homolog 2 (EZH2) and Global H3K27 Trimethylation Expression During Progression of Thyroid Cancer

none7siBackground: EZH2 is a histone lysine methyltransferase that is a member of the polycomb group protein family. EZH2 plays an important role in the epigenetic maintenance of H3K27 trimethylation (H3K27me3). Abnormal EZH2 expression has been associated with various cancers. We examined the expression of EZH2 and H3K27me3 to determine their roles in thyroid cancer progression. Design: Anaplastic thyroid carcinomas (ATC, n=35), poorly differentiated thyroid carcinomas (PDTC, n=21), papillary thyroid carcinomas (PTC, n=28), follicular variant of papillary thyroid carcinomas (FVPTC, n=29), follicular thyroid carcinomas (FTC, n=28), follicular adenomas (FA, n=31) and normal thyroids (NT, n=10) on a tissue microarray (TMA) were analyzed by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded tissues. Antibodies to EZH2 (Novus, 1:100) and H3K27me3 (Cell Signaling, 1:200) were used. IHC was scored based on the intensity and percentage of nuclear staining. Survival analysis was performed using the statistical computing software R. Results: Both EZH2 and H3K27me3 showed strong nuclear staining. The highest level of EZH2 expression was observed in ATC (97%) followed by PDTC (90%). Levels were lower in FA (71%), FTC (64%), PTC (79%) and FVPTC (79%). EZH2 expression was significantly higher in ATC than in well-differentiated carcinomas (P<0.04). H3K27me3 expression was high in both benign and malignant thyroid tumors as well as in NT. H3K27me3 expression was not significantly different in higher-grade tumors compared to well-differentiated carcinomas and FA. The carcinoma types expressing the highest levels of EZH2 (ATC and PDTC) had worse prognoses than the carcinoma types with lower expression (P<0.001). Conclusions: EZH2 is expressed in thyroid malignancies, and its expression correlates with higher-grade tumors. EZH2 effects may also include H3K27me3-independent mechanisms. Our findings suggest that EZH2 may play an important role in thyroid tumor progression.mixedSundling, Kaitlin; Montemayor-Garcia, Celina; Hardin, Heather; Buehler, Darya; Asioli, Sofia; Righi, Alberto; Lloyd, Ricardo .Sundling, Kaitlin; Montemayor-Garcia, Celina; Hardin, Heather; Buehler, Darya; Asioli, Sofia; Righi, Alberto; Lloyd, Ricardo

MODELING THE ENDOCRINE CONTROL OF VITELLOGENIN PRODUCTION IN FEMALE RAINBOW TROUT

The rainbow trout endocrine system is sensitive to changes in annual day length, which is likely the principal environmental cue controlling its reproductive cycle. This study focuses on the endocrine regulation of vitellogenin (Vg) protein synthesis, which is the major egg yolk precursor in this fish species. We present a model of Vg production in female rainbow trout which incorporates a biological pathway beginning with sex steroid estradiol-17β levels in the plasma and concluding with Vg secretion by the liver and sequestration in the oocytes. Numerical simulation results based on this model are compared with experimental data for estrogen receptor mRNA, Vg mRNA, and Vg in the plasma from female rainbow trout over a normal annual reproductive cycle. We also analyze the response of the model to parameter changes. The model is subsequently tested against experimental data from female trout under a compressed photoperiod regime. Comparison of numerical and experimental results suggests the possibility of a time-dependent change in oocyte Vg uptake rate. This model is part of a larger effort that is developing a mathematical description of the endocrine control of reproduction in female rainbow trout. We anticipate that these mathematical and computational models will play an important role in future regulatory toxicity assessments and in the prediction of ecological risk