Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Cancer Sci. 2011 Apr;102(4):776-83. doi: 10.1111/j.1349-7006.2011.01848.x. Epub 2011 Feb 10.
RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region frequently inactivated through hypermethylation, histone modulation, and other processes in various human tumors. In this study, to elucidate a causal link between RUNX3 expression and biliary tract cancer, we investigated 17 human biliary cancer specimens. In addition, to examine roles of RUNX3 in biliary tract cancer, we restored silenced RUNX3 in the human biliary cancer cell line Mz-ChA-2 using a histone deacetylase inhibitor. Thirteen of 17 human cancer specimens exhibited suppressed RUNX3 expression compared with normal biliary ducts. Moreover, the decreased RUNX3 expression was related to a lower accumulation of acetylated histone H3 associated with RUNX3. In in vitro experiments, vorinostat, a member of a new class of highly potent histone deacetylase inhibitors, restored RUNX3 expression in Mz-ChA-2 cells. Furthermore, vorinostat-induced RUNX3 significantly enhanced p21 expression and growth inhibition of Mz-ChA-2 cells through restoration of TGF-β signaling. These data suggest the significance of histone deacetylation-associated suppression of RUNX3 expression in biliary tract carcinogenesis. Furthermore, vorinostat might hold promise for treating biliary tract cancer through enhancement of TGF-β signaling by restoration of RUNX3.
RUNX3 是一个候选肿瘤抑制基因，位于 1p36 上，该区域经常因过度甲基化、组蛋白修饰和其他过程而失活，存在于多种人类肿瘤中。在这项研究中，为了阐明 RUNX3 表达与胆管癌之间的因果关系，我们研究了 17 个人类胆管癌标本。此外，为了研究 RUNX3 在胆管癌中的作用，我们使用组蛋白去乙酰化酶抑制剂在人胆管癌细胞系 Mz-ChA-2 中恢复沉默的 RUNX3。与正常胆管相比，17 个人类癌症标本中有 13 个表现出 RUNX3 表达受抑制。此外，RUNX3 表达的减少与 RUNX3 相关的乙酰化组蛋白 H3 的积累减少有关。在体外实验中，组蛋白去乙酰化酶抑制剂伏立诺他可恢复 Mz-ChA-2 细胞中 RUNX3 的表达。此外，伏立诺他诱导的 RUNX3 通过恢复 TGF-β 信号显著增强了 Mz-ChA-2 细胞中 p21 的表达和生长抑制。这些数据表明，在胆管癌发生过程中，组蛋白去乙酰化相关的 RUNX3 表达抑制具有重要意义。此外，通过恢复 RUNX3 增强 TGF-β 信号，伏立诺他可能有望用于治疗胆管癌。
