Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer.
Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer.
复制标题
DOI：
10.1158/1940-6207.capr-11-0267
复制
发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Dahiya R
中科院分区：
文献类型：
--
作者：
Saini S;Arora S;Majid S;Shahryari V;Chen Y;Deng G;Yamamura S;Ueno K;Dahiya R
膀胱癌通常与复发和进展为具有姑息治疗选择的侵袭性转移性疾病相关。使用传统的化疗药物治疗膀胱癌往往会出现毒性和耐药性问题。这强调了需要开发更安全、天然、无毒的化合物作为化学治疗/化学预防剂。姜黄素（二阿魏酰甲烷）是一种天然化合物，已知在各种癌症中具有抗癌特性，包括膀胱癌。然而，姜黄素的生物学靶点并没有很好地定义。最近，已经提出姜黄素可以介导microRNA（miRNAs）表达的表观遗传调节。在这份报告中，我们首次定义了姜黄素在膀胱癌中直接诱导肿瘤抑制性miRNA miR-203。miR-203在膀胱癌中由于其启动子的DNA而频繁下调。我们研究了miR-203在膀胱癌细胞系中的功能意义，发现miR-203具有肿瘤抑制特性。此外，我们将Akt 2和Src定义为膀胱癌中miR-203的新靶点。姜黄素诱导miR-203启动子的低甲基化和随后的miR-203表达上调。这导致miR-203靶基因Akt 2和Src的下调，最终导致膀胱癌细胞增殖减少和凋亡增加。这是第一份显示姜黄素对诱导miRNA启动子处的表观遗传变化具有直接生物学后果的直接作用的报告。我们的研究表明，姜黄素在难治性膀胱癌的临床治疗中可能比其他标准治疗方式具有治疗优势。
Bladder cancer is often associated with recurrence and progression to invasive metastatic disease that have palliative therapeutic options. The use of traditional chemotherapeutic agents for bladder cancer management often suffer from toxicity and resistance concerns. This emphasizes the need for development of safer, natural, non-toxic compounds as chemotherapeutic/chemopreventive agents. Curcumin (diferuloylmethane) is a natural compound that has been known to possess anti-cancer properties in various cancers, including bladder cancer. However, the biological targets of curcumin are not well defined. Recently, it has been proposed that curcumin may mediate epigenetic modulation of expression of microRNAs (miRNAs). In this report, we define for the first time, that curcumin directly induces a tumor-suppressive miRNA, miR-203, in bladder cancer. miR-203 is frequently downregulated in bladder cancer due to DNA of its promoter. We studied the functional significance of miR-203 in bladder cancer cell lines and found that miR-203 has tumor suppressive properties. Also, we define Akt2 and Src as novel miR-203 targets in bladder cancer. Curcumin induces hypomethylation of the miR-203 promoter and subsequent upregulation of miR-203 expression. This leads to downregulation of miR-203 target genes Akt2 and Src that culminates in decreased proliferation and increased apoptosis of bladder cancer cells. This is the first report that shows a direct effect of curcumin on inducing epigenetic changes at a miRNA promoter with direct biological consequences. Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities.