miR-618调控FOXP2影响AIPC转移的研究

Previously, pair-wise significance analysis of the microarray data indicated that the expression of miR-618 was significantly down-regulated in androgen-independent prostate cancer(AIPC) compared to those in androgen-dependent prostate cancer(ADPC). Furthermore, our preliminary data showed that miR-618 suppress the metastasis of androgen-independent prostate cancer cells via repressing the epithelial-mesenchymal transition(EMT). Moreover, integration of the results of bioinformatic analysis and biological experiments revealed that miR-618 downregulated FOXP2 by directly targeting its 3'untranslated region (3`-UTR) to inhibit the transcriptional activity of TGF-β and suppress the activity of TGF-β/Smad pathway, resulting in an inhibition of metastasis effect in androgen-independent prostate cancer cells. These results suggest that miR-618 plays an important role in prostate cancer metastasis. Hence, in the current project, we aim to employ immuno-fluorence staining, western blot and luciferase reporter assays in both in vitro and in vivo systems and use clinical samples to further investigate the mechanism by which miR-618 represses metastasis, in order to provide new biomarkers and targets for the diagnosis and treatment of prostate cancer.

我们采用MicroRNA芯片技术发现miR-618在AIPC中表达比ADPC明显降低。预实验显示miR-618抑制细胞的EMT而阻止细胞转移侵袭。生物信息学及实验结果表明miR-618可直接抑制FOXP2表达，进而下调TGF-β转录活性、抑制TGF-β/Smad通路活性从而调控细胞转移侵袭，但具体机制尚待阐明。本项目将以过表达或抑制miR-618的雄性激素非依赖性细胞为模型，研究miR-618抑制细胞转移侵袭的分子机制,探讨miR-618下调FOXP2/抑制TGF-β转录活性/抑制TGF-β/Smad通路活性的分子机制。并拟通过在肿瘤动物模型确定miR-618抑制肿瘤转移侵袭的功能，进而在临床研究中验证miR-618与前列腺癌转移相关性。本研究将为miR-618通过直接调控FOXP2/TGF-β/Smad 信号通路而抑制肿瘤转移侵袭的科学假说提供证据，并为前列腺癌诊断治疗提供新的分子靶点。

前列腺癌（prostate cancer，Pca）是男性最常见的恶性肿瘤之一，在西方发达国家其死亡率仅次于肺癌。PCa早期大多具有雄性激素依赖的生物学特征，可以通过剥夺雄性激素疗法使患者得到有效的治疗。但这种治疗方法并不能根治癌症，只能让患者得到平均14～20个月的休整期，之后患者几乎都会发展成雄性激素非依赖性前列腺癌（Androgen-Independent Prostate Cancer, AIPC），并最终死于癌症的转移。临床研究发现，AIPC比雄性激素依赖性前列腺癌（Androgen-Dependent Prostate Cancer，ADPC）的转移能力更高，然而，目前为止其分子机制尚未被阐明。阐明AIPC获得高转移能力分子机制，将对于前列腺癌的治疗和药物研制具有重要指导意义我们采用MicroRNA芯片技术发现miR-618在AIPC中表达比ADPC明显降低。预实验显示miR-618抑制细胞的EMT而阻止细胞转移侵袭。生物信息学及实验结果表明miR-618可直接抑制FOXP2表达，进而下调TGF-β转录活性从而调控细胞转移侵袭，但具体机制尚待阐明。本项目将以过表达或抑制miR-618的雄性激素非依赖性细胞为模型，研究miR-618抑制细胞转移侵袭的分子机制,探讨miR-618下调FOXP2/抑制TGF-β转录活性的分子机制。进而在临床研究中验证miR-618与前列腺癌转移相关性。本研究将为miR-618通过直接调控FOXP2/TGF-β 信号通路而抑制肿瘤转移侵袭的科学假说提供证据，并为前列腺癌诊断治疗提供新的分子靶点。