Saito Yoshimasa, Hibino Sana, Saito Hidetsugu
Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hepatol Res. 2014 Jan;44(1):31-42. doi: 10.1111/hepr.12147. Epub 2013 May 26.
Studies have shown that alterations of epigenetics and microRNA (miRNA) play critical roles in the initiation and progression of hepatocellular carcinoma (HCC). Epigenetic silencing of tumor suppressor genes in HCC is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9) and tri-methylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have shown clinical promise for cancer therapy. miRNA are small non-coding RNA that regulate expression of various target genes. Specific miRNA are aberrantly expressed and play roles as tumor suppressors or oncogenes during hepatocarcinogenesis. We and other groups have demonstrated that important tumor suppressor miRNA are silenced by epigenetic alterations, resulting in activation of target oncogenes in human malignancies including HCC. Restoring the expression of tumor suppressor miRNA by inhibitors of DNA methylation and histone deacetylase may be a promising therapeutic strategy for HCC.
研究表明，表观遗传学和微小RNA（miRNA）的改变在肝细胞癌（HCC）的发生和发展中起着关键作用。HCC中肿瘤抑制基因的表观遗传沉默通常由CpG岛启动子的DNA高甲基化和组蛋白修饰介导，如组蛋白去乙酰化、组蛋白H3赖氨酸9（H3K9）甲基化和H3K27三甲基化。诸如DNA甲基化抑制剂和组蛋白脱乙酰酶抑制剂等染色质修饰药物已显示出在癌症治疗中的临床前景。miRNA是调节各种靶基因表达的小非编码RNA。特定的miRNA在肝癌发生过程中异常表达，并作为肿瘤抑制因子或癌基因发挥作用。我们和其他研究小组已经证明，重要的肿瘤抑制miRNA会因表观遗传改变而沉默，从而导致包括HCC在内的人类恶性肿瘤中靶癌基因的激活。通过DNA甲基化和组蛋白脱乙酰酶抑制剂恢复肿瘤抑制miRNA的表达可能是HCC一种有前景的治疗策略。
