金雀异黄素通过靶向 miR-34a 和致癌基因 HOTAIR 抑制前列腺癌细胞生长。
Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR.
机构信息
Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
出版信息
PLoS One. 2013 Aug 1;8(8):e70372. doi: 10.1371/journal.pone.0070372. Print 2013.
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.
目的
染料木黄酮是一种大豆异黄酮，具有体外和体内抗肿瘤活性。已经表明染料木黄酮通过调节几种细胞信号通路和 microRNAs（miRNAs）来抑制多种类型的癌症，包括前列腺癌（PCa）。最近的研究表明，长链非编码 RNA（lncRNAs）也参与许多细胞过程。目前尚无关于染料木黄酮、miRNAs 和 lncRNAs 之间关系的报道。在这项研究中，我们专注于受染料木黄酮调节的 miRNAs 和 lncRNAs，并研究了它们在 PCa 中的功能作用。
方法
使用微阵列（SurePrint G3 Human GE 8×60K）对染料木黄酮处理和对照 PCa 细胞（PC3 和 DU145）进行表达谱分析。使用 PCa 细胞系 PC3 和 DU145 进行功能测定（细胞增殖、迁移、侵袭、凋亡和细胞周期测定）。使用体外和体内（裸鼠）模型进行生长测定。荧光素酶报告基因测定用于 miR-34a 与 HOTAIR 的结合。
结果
lncRNA 分析表明，HOTAIR 受染料木黄酮的高度调节，其在去势抵抗性 PCa 细胞系中的表达高于正常前列腺细胞。HOTAIR 的敲低（siRNA）降低了 PCa 细胞的增殖、迁移和侵袭，并诱导了细胞凋亡和细胞周期停滞。miR-34a 也被染料木黄酮上调，并且可能在 PC3 和 DU145 PCa 细胞中直接靶向 HOTAIR。
结论
我们的结果表明，染料木黄酮通过下调致癌基因 HOTAIR 抑制 PCa 细胞生长，而 HOTAIR 也是肿瘤抑制 miR-34a 的靶标。这些发现增强了对染料木黄酮如何调节 PCa 中的 lncRNA HOTAIR 和 miR-34a 的理解。
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