Angiomotin调控Hippo-YAP信号通路在前列腺癌进展中的生物学意义

Angiomotin (AMOT) belongs to a novel protein family that regulates endothelial cell migration and tube formation by binding to angiostatin. The role of AMOT in tumor has been rarely investigated. Whether AMOT plays a role in prostate cancer and its signals in prostate cancer are unknown. In our previous study, we have found that AMOTp80 (one of two AMOT isoforms) functioned as a tumor promoter by enhancing prostate cancer cell proliferation. And further study suggested that: Hippo-YAP signaling may have closely relationship with AMOT in prostate cancer and may be controlled by AMOT interacting with Merlin. Based on the analysis mentioned above and the results of our previous study, we are the first to propose the following hypothesis: the abnormal expression of AMOT may be an important molecular mechanism of Hippo-YAP signaling pathway in prostate cancer progression, and AMOT may regulate Hippo-YAP pathway through the interaction with Merlin. In the present study, we prospected to confirm the potential role of AMOT and its significance in prostate cancer, clarify the control mechanism of AMOT-Merlin-Hippo-YAP-target genes pathway in the progression of prostate cancer, and explore a novel idea for future study by using various molecular biology technologies.

Angiomotin（AMOT）是近年来新发现的一种血管肌动蛋白，主要参与调节内皮细胞迁移及小管形成，但其是否参与调控肿瘤演进及其调控机制方面的研究几乎没有。本研究小组前期研究发现，AMOT与前列腺癌细胞增殖相关，并且其分子机制可能与AMOT通过与Merlin的相互作用间接调控Hippo信号通路相关。结合本研究小组前期工作及国内外相关研究，本课题首次提出：在前列腺癌中，AMOT可能通过与Merlin的相互作用间接调控Hippo-YAP信号通路介导前列腺癌细胞演进，AMOT的异常表达与前列腺癌的进展及预后相关。本课题小组拟运用多种分子生物学技术，证实AMOT参与调控前列腺癌演进的重要作用，并阐明AMOT-Merlin-Hippo-YAP-靶基因信号通路是前列腺癌进展的重要调控机制，从而为前列腺癌进展机制的研究提供新的思路。

Angiomotin（AMOT）是近年来新发现的一种血管肌动蛋白。它在前列腺癌中的意义尚不清楚。本研究的目的在于探索AMOT的不同亚型在前列腺肿瘤增殖过程中的作用。AMOT有两种亚型：AMOTp80和AMOTp130。AMOTp130中有一个由409个氨基酸组成的N-末端结构域，这个结构域是AMOTp80不具有的。通过real-time PCR和Western blot技术我们发现AMOTp80和AMOTp130在LNCaP和C4-2B4细胞中都有表达，但是在PC3、DU145和BPH1细胞中则是低表达或不表达。通过双顺反子逆转录病毒将AMOTp80 cDNA转导入PC3-mm2细胞后，细胞的增殖能力明显增强，但迁移能力无显著变化。而在导入AMOTp80和AMOTp130后，PC3-mm2细胞也出现了增殖能力的增强，但弱于只导入AMOTp80的细胞。在导入AMOTp130后PC3-mm2细胞的增殖能力则无明显变化。通过shRNA沉默C4-2B4细胞中AMOT表达后，C4-2B4细胞的增殖能力下降，但其迁移能力无明显改变。机制研究表明AMOTp80的过表达可以抑制Hippo信号通路中MST1-pLATS-pYAP的水平。AMOTp80能通过促进YAP的核转位而在Hippo信号通路中起作用，并导致YAP的靶蛋白BMP4表达升高。此外，通过LDN-193189抑制BMP4受体活性能够阻止AMOTp80所介导的细胞增殖。总结而言，我们发现AMOTp80和AMOTp130在前列腺癌细胞中有不同的功能。AMOTp80，而不是AMOTp130能通过增强细胞的增殖能力来促进肿瘤发展。这项研究还揭露了一个新型的信号通路AMOTp80-Merlin-MST1-LATS-YAP-BMP4，这条信号通路最终导致前列腺肿瘤细胞的增殖。