Plos One, 2013, 8(8):343-9.

Genistein Inhibits Prostate Cancer Cell Growth by Targeting miR-34a and Oncogenic HOTAIR

Takeshi Chiyomaru, Soichiro Yamamura, Shinichiro Fukuhara, et al

Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America; et al

OBJECTIVE:

Genistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa) by regulating several cell signaling pathways and microRNAs (miRNAs). Recent studies suggest that the long non-coding RNAs (lncRNAs) are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa.

METHOD:

Microarray (SurePrint G3 Human GE 8×60K) was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145). Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays) were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse) models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR.

RESULTS:

LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.

CONCLUSIONS:

Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa.

美国《公共科学图书馆一》，2013年8月

金雀异黄素通过靶向miR-34a 和致癌基因HOTAIR抑制前列腺癌细胞的生长

千与丸刚志，柳屋庄一郎，福原一郎，等

美国旧金山退伍军人事务医学中心和加利福尼亚大学泌尿外科等

目的︰

金雀异黄素是一种在体外和体内具有抗肿瘤活性的大豆异黄酮。已表明，金雀异黄素通过调节几种细胞信号通路和微RNAs (miRNAs)等抑制包括前列腺癌 (PCa)的许多类型的癌症。最近的研究表明，长链非编码 RNAs (lncRNAs) 也参与了许多细胞过程。目前没有关于 金雀异黄素，miRNAs 与 lncRNAs 之间关系的报告。在此研究中，我们集中研究由金雀异黄素调节的miRNA，lncRNA，并探究它们对 PCa 的作用。

方法︰

基因芯片 (SurePrint G3 人体  GE 8 × 60K) 被用于金雀异黄素治疗和控制 PCa 细胞（PC3和 DU145）的表达谱。用PCa，PC3 和 DU145细胞进行了功能的测定 （细胞增殖、 迁移、 入侵、 细胞凋亡和细胞周期检测）。体外和体内的 （裸鼠） 模型被用于生长测试。荧光素酶记录测试被用于miR-34a 到HOTAIR的绑定。

结果︰

LncRNA 分析表明，HOTAIR受到金雀异黄素的高度调节并且其在去势难治性的 PCa 细胞比正常的前列腺细胞表达更高。HOTAIR的组合降低了PCa 细胞的增殖、 迁移与侵袭和诱导细胞凋亡及细胞周期阻滞。miR-34a 也由金雀异黄素上调，并且在PC3 和 DU145 PCa 细胞中可能直接靶向HOTAIR。

结论︰

我们的研究结果表明，金雀异黄素通过下调致癌因子HOTAIR（通常也是肿瘤抑制剂miR-34a的靶标）抑制PCa 细胞的生长。这些发现加深了对金雀异黄素调节PCa中 lncRNA  HOTAIR和 miR-34a的认识 。