Saito Yoshimasa, Nakaoka Toshiaki, Saito Hidetsugu
Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
J Clin Med. 2015 Nov 16;4(11):1951-9. doi: 10.3390/jcm4111951.
microRNAs (miRNAs) are small non-coding RNAs that down-regulate expression of various target genes. Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis. We and other researchers have demonstrated that important tumor suppressor miRNAs are silenced by epigenetic alterations, resulting in the activation of target oncogenes in cancer cells. miR-34a was identified as a target of p53 and induces a G1 cell cycle arrest, senescence and apoptosis in response to DNA damage. miR-34a is an important tumor suppressor whose expression is epigenetically silenced in various human cancers. Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells. Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies. Restoring of miR-34a expression by epigenetic therapy and/or delivery of miR-34a mimics may be a promising therapeutic strategy against human cancer.
微小RNA（miRNA）是一类小的非编码RNA，可下调各种靶基因的表达。与癌症相关的miRNA表达异常，在致癌过程中充当肿瘤抑制因子或癌基因。我们和其他研究人员已经证明，重要的肿瘤抑制性miRNA会因表观遗传改变而沉默，从而导致癌细胞中靶癌基因的激活。miR-34a被确定为p53的靶标，并在DNA损伤时诱导G1期细胞周期停滞、衰老和凋亡。miR-34a是一种重要的肿瘤抑制因子，其表达在多种人类癌症中通过表观遗传机制被沉默。强制表达miR-34a可诱导细胞周期停滞、凋亡、衰老，并抑制上皮-间质转化，还能抑制癌症干细胞的增殖。使用诸如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进行表观遗传治疗，已显示出治疗恶性肿瘤的临床前景。通过表观遗传治疗恢复miR-34a的表达和/或递送miR-34a模拟物可能是一种有前景的治疗人类癌症的策略。
