1). The nuclear receptor corepressor (NCOR1) acts as an oncogene in a mouse model of thyroid cancer Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. We elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (TRbetaPV/PV mice) that spontaneously develops thyroid cancer. We adopted the loss-of-the function approach by crossing TRbetaPV/PV mice with mice that globally express an NCOR1 mutant protein (NCOR1deltaID) in which the receptor interaction domains have been modified so that it cannot interact with the TRbeta, or PV, in mice. Remarkably, expression of NCOR1deltaID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of TRbetaPV/PVNCOR1deltaID/deltaID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1, p21 and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X and PUMA. Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the p21 and the BAX gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the p21 and BAX gene in thyroids of TRbetaPV/PV mice. In thyroids of TRbetaPV/PVNCOR1deltaID/deltaID mice, the p53/PV complex could not recruit NCOR1deltaID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer. 2). Uncovering three-dimensional telomere dynamics in follicular thyroid cancer. To understand genomic mechanisms impact thyroid carcinogenesis, we used quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in the thyroid of wild-type mice, homozygous, and heterozygous TRbetaPV mice. The comparison was made before and after the homozygous TRbetaPV/PV mice developed thyroid cancer. Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloViewimage analysis, we found altered telomeric signatures specifically in thyroid tumors of TRbetaPV/PV mice. As early as 1 month of age, TRbetaPV/PV mice thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of TRbetaPV/PV mouse nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in TRbetaPV/PV mouse well before the presentation of histological signs of thyroid carcinoma. Thus, we showed that quantitative 3D telomere analysis is a novel tool for early detection and monitoring of thyrocyte chromosomal (un)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.
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