Ferrario Cristina, Lavagni Paola, Gariboldi Manuela, Miranda Claudia, Losa Marco, Cleris Loredana, Formelli Franca, Pilotti Silvana, Pierotti Marco A, Greco Angela
Operative Unit Molecular Mechanisms of Cancer Growth and Progression, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Lab Invest. 2008 May;88(5):474-81. doi: 10.1038/labinvest.2008.17. Epub 2008 Mar 10.
The molecular pathogenesis of tumors arising from the thyroid follicular epithelial cells, including papillary (PTC) and follicular thyroid carcinoma (FTC), is only partially understood, and the role of tumor suppressor genes has not yet been assessed. The metallothionein (MT) gene family encodes a class of metal-binding proteins involved in several cellular processes, and their expression is often deregulated in human tumors. Recently, downregulation of MT gene expression in PTC has been reported, suggesting a possible oncosuppressor role of this gene family in the pathogenesis of thyroid tumors. To further explore this possibility, we performed expression and functional studies. Analysis of microarray data of thyroid tumors of different histologic types showed that several MT genes were downregulated with respect to normal tissue. The microarray data were corroborated by quantitative PCR experiments, showing downregulation of MTs in PTC and FTC, but to a greater extent in papillary carcinoma. The expression of MTs was also investigated at the protein level by immunohistochemistry; the results were consistent with the microarray data, showing general downregulation in tumor samples, which was more evident in PTC. The functional consequence of MT downregulation was addressed employing an experimental model made of the PTC-derived K1 cell line in which MT1G expression is repressed by promoter methylation. Restoration of MT1G expression by cDNA transfection affected growth rate and in vivo tumorigenicity of K1 cells, indicating an oncosuppressor role for MT1G in thyroid papillary tumorigenesis.
甲状腺滤泡上皮细胞来源的肿瘤，包括乳头状甲状腺癌（PTC）和滤泡状甲状腺癌（FTC）的分子发病机制仅得到部分了解，肿瘤抑制基因的作用尚未得到评估。金属硫蛋白（MT）基因家族编码一类参与多种细胞过程的金属结合蛋白，其表达在人类肿瘤中常常失调。最近，有报道称PTC中MT基因表达下调，提示该基因家族在甲状腺肿瘤发病机制中可能具有肿瘤抑制作用。为了进一步探究这种可能性，我们进行了表达和功能研究。对不同组织学类型的甲状腺肿瘤微阵列数据的分析表明，相对于正常组织，几个MT基因表达下调。定量PCR实验证实了微阵列数据，显示PTC和FTC中MT表达下调，但在乳头状癌中下调程度更大。还通过免疫组织化学在蛋白质水平研究了MT的表达；结果与微阵列数据一致，显示肿瘤样本中普遍下调，在PTC中更明显。利用由PTC来源的K1细胞系构建的实验模型探讨了MT下调的功能后果，在该模型中MT1G表达因启动子甲基化而受到抑制。通过cDNA转染恢复MT1G表达影响了K1细胞的生长速率和体内致瘤性，表明MT1G在甲状腺乳头状肿瘤发生中具有肿瘤抑制作用。
