Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Oncogene. 2013 Aug 22;32(34):4052-6. doi: 10.1038/onc.2012.407. Epub 2012 Sep 17.
Current genetic evidence in mice indicates that SIRT1 has potent tumor suppressor activity in a variety of cancer models, with no evidence yet for SIRT1 oncogenic activity in vivo. We report here that transgenic Sirt1 expression is oncogenic in murine thyroid and prostate carcinogenesis initiated by Pten-deficiency. Based on mRNA expression analyses of pre-tumoral murine thyroids, we find that SIRT1 increases c-MYC transcriptional programs. Moreover, we show higher c-MYC protein levels in murine thyroid cancers from Sirt1 transgenic mice. Similarly, SIRT1 is overexpressed in human thyroid cancers and it is positively correlated with c-MYC protein levels. Finally, we show in cultured thyroid cancer cells that SIRT1 stabilizes c-MYC protein. These results implicate SIRT1 as a new candidate target for the treatment of thyroid carcinomas.
目前在小鼠中的遗传证据表明，SIRT1 在多种癌症模型中具有强大的肿瘤抑制活性，目前尚无体内 SIRT1 致癌活性的证据。我们在这里报告，转基因 Sirt1 表达在由 Pten 缺失引发的小鼠甲状腺和前列腺癌发生中具有致癌性。基于对前肿瘤性小鼠甲状腺的 mRNA 表达分析，我们发现 SIRT1 增加了 c-MYC 转录程序。此外，我们在 Sirt1 转基因小鼠的小鼠甲状腺癌中显示出更高的 c-MYC 蛋白水平。同样，SIRT1 在人类甲状腺癌中过度表达，并且与 c-MYC 蛋白水平呈正相关。最后，我们在培养的甲状腺癌细胞中表明 SIRT1 稳定 c-MYC 蛋白。这些结果表明 SIRT1 是治疗甲状腺癌的新候选靶标。
