Ying Hao, Suzuki Hideyo, Furumoto Hiroko, Walker Robert, Meltzer Paul, Willingham Mark C, Cheng Sheue-Yann
Laboratory of Molecular Biology, National Cancer Institute, Winston-Salem, NC 27157-1072, USA.
Carcinogenesis. 2003 Sep;24(9):1467-79. doi: 10.1093/carcin/bgg111. Epub 2003 Jul 17.
The molecular genetics underlying thyroid carcinogenesis is not well understood. We have recently created a mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse). TRbetaPV/PV mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia and eventually metastasis to distant organs. TRbetaPV/PV mice provide an unusual opportunity to study the alterations in gene regulation that occur during thyroid carcinogenesis. To this end, we profiled the genomic changes in the thyroids of TRbetaPV/PV mice at 6 months of age, at which time metastasis had begun. From arrays of 20 000 mouse cDNAs, 185 genes were up-regulated (2-17-fold) and 92 were down-regulated (2-20-fold). Functional clustering of named genes with reported functions (100 genes) indicated that approximately 39% of these genes were tumor-, metastasis/invasion- and cell-cycle-related. Among the activated tumor-related genes identified, cyclin D1, pituitary tumor transforming gene-1, cathespin D and transforming growth factor alpha were also found to over-express in human thyroid cancers. Analyses of the gene profiles suggested that the signaling pathways mediated by thyrotropin, peptide growth factors, transforming growth factor-beta, tumor necrosis factor-alpha and nuclear factor-kappaB were activated, whereas pathways mediated by peroxisome proliferation activated receptor gamma were repressed. These results indicate that complex alterations of multiple signaling pathways contribute to thyroid carcinogenesis. The critical genes associated with thyroid follicular carcinogenesis uncovered in the present study could serve as signature genes for diagnostic purposes, as well as for possible therapeutic targets.
甲状腺癌发生的分子遗传学机制尚未完全明确。我们最近通过在甲状腺激素受体β基因中靶向引入一个突变（PV），培育出了一种突变小鼠（TRbetaPV小鼠）。TRbetaPV/PV小鼠会通过增生、包膜和血管浸润、间变，最终转移至远处器官的病理进程，自发形成滤泡状甲状腺癌。TRbetaPV/PV小鼠为研究甲状腺癌发生过程中基因调控的变化提供了一个独特的机会。为此，我们对6月龄TRbetaPV/PV小鼠甲状腺中的基因组变化进行了分析，此时转移已经开始。在20000个小鼠cDNA阵列中，185个基因上调（2至17倍），92个基因下调（2至20倍）。对具有已知功能的命名基因（100个基因）进行功能聚类分析表明，这些基因中约39%与肿瘤、转移/侵袭和细胞周期相关。在鉴定出的激活的肿瘤相关基因中，还发现细胞周期蛋白D1、垂体肿瘤转化基因-1、组织蛋白酶D和转化生长因子α在人类甲状腺癌中也过表达。基因谱分析表明，促甲状腺激素、肽生长因子、转化生长因子-β、肿瘤坏死因子-α和核因子-κB介导的信号通路被激活，而过氧化物酶体增殖物激活受体γ介导的通路被抑制。这些结果表明，多种信号通路的复杂改变参与了甲状腺癌的发生。本研究中发现的与甲状腺滤泡癌发生相关的关键基因，可作为诊断的特征基因以及可能的治疗靶点。
