Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Oncogene. 2010 Apr 1;29(13):1909-19. doi: 10.1038/onc.2009.476. Epub 2010 Jan 11.
Aberrant expression and mutations of thyroid hormone receptor genes (TRs) are closely associated with several types of human cancers. To test the hypothesis that TRs could function as tumor suppressors, we took advantage of mice with deletion of all functional TRs (TRalpha1(-/-)TRbeta(-/-) mice). As these mice aged, they spontaneously developed follicular thyroid carcinoma with pathological progression from hyperplasia to capsular invasion, vascular invasion, anaplasia and metastasis to the lung, similar to human thyroid cancer. Detailed molecular analysis revealed that known tumor promoters such as pituitary tumor-transforming gene were activated and tumor suppressors such as peroxisome proliferator-activated receptor gamma and p53 were suppressed during carcinogenesis. In addition, consistent with the human cancer, AKT-mTOR-p70(S6K) signaling and vascular growth factor and its receptor were activated to facilitate tumor progression. This report presents in vivo evidence that functional loss of both TRalpha1 and TRbeta genes promotes tumor development and metastasis. Thus, TRs could function as tumor suppressors in a mouse model of metastatic follicular thyroid cancer.
甲状腺激素受体基因（TRs）的异常表达和突变与多种人类癌症密切相关。为了验证 TRs 可以作为肿瘤抑制因子发挥作用的假说，我们利用了所有功能性 TR 缺失的小鼠（TRalpha1(-/-)TRbeta(-/-) 小鼠）。随着这些小鼠年龄的增长，它们会自发地发展为滤泡性甲状腺癌，其病理进程从增生发展到包膜浸润、血管浸润、间变和向肺部转移，类似于人类甲状腺癌。详细的分子分析显示，在癌变过程中，已知的肿瘤促进因子如垂体肿瘤转化基因被激活，而肿瘤抑制因子如过氧化物酶体增殖物激活受体 γ 和 p53 被抑制。此外，与人类癌症一致，AKT-mTOR-p70(S6K)信号和血管生长因子及其受体被激活，以促进肿瘤进展。本报告提供了体内证据，证明功能性的 TRalpha1 和 TRbeta 基因缺失会促进肿瘤的发展和转移。因此，TRs 可能在转移性滤泡性甲状腺癌的小鼠模型中作为肿瘤抑制因子发挥作用。
