Thyroid hormone receptors and cancer.
Thyroid hormone receptors and cancer.
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DOI：
10.1016/j.bbagen.2012.04.002
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发表时间：
2013-07
影响因子：
3
通讯作者：
Cheng, Sheue-yann
中科院分区：
文献类型：
--
作者：
Kim, Won Gu;Cheng, Sheue-yann
关键词：
甲状腺激素受体（TRs）是介导甲状腺激素（T3）在发育、生长和分化中的作用的配体依赖性转录因子。THRA和THRB基因编码以组织和发育依赖性方式表达的几种TR亚型。在过去的几十年里，在理解TR在维持正常细胞功能中的作用方面取得了重大进展。然而，TRs在人类癌症中的作用还不太清楚。由于人类癌症中发现的TR基因的高甲基化或缺失而导致的TR表达减少表明TR可以作为肿瘤抑制因子发挥作用。TR的体细胞突变与人类癌症的密切关联进一步支持了TR正常功能的丧失可能导致不受控制的生长和细胞分化的丧失的观点。与人类癌症相关性研究的结果一致，总功能TR缺陷小鼠（Thra 1 −/−Thrb−/−小鼠）或Thrb基因靶向纯合突变小鼠（表示为PV; ThrbPV/PV小鼠）自发发生转移性甲状腺癌。这篇综述将研究从这些基因工程小鼠中获得的证据，这些证据提供了强有力的证据来支持TRs在人类癌症中的关键作用。TR缺失或突变导致的正常功能丧失可能导致癌症的发生、进展和转移。揭示了异常TR活动如何导致癌变的新机制见解。甲状腺癌的小鼠模型提供了确定分子靶点作为潜在治疗方式的机会。
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TRs in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation. In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1−/−Thrb−/− mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; ThrbPV/PV mice) spontaneous develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer. Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis. Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities.
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影响因子：
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