Department of Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Infectious Disease, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.
J Cell Biochem. 2019 Apr;120(4):4987-4997. doi: 10.1002/jcb.27774. Epub 2018 Oct 9.
Deregulation of microRNAs contributes to the abnormal cell growth which is frequently observed in cancer. In the current study, we detected the expression and regulatory relationship between miR-10a and Lysine-specific demethylase 4A (KDM4A) to reveal their function in prostate cancer (PCa) progression. We found that miR-10a levels were significantly decreased in PCa cell lines in comparison with the normal epithelial cell line RWPE-1. Downregulation of miR-10a levels was also observed in tumor tissues from PCa patients compared with the adjacent normal tissues. Enhanced expression of miR-10a inhibited cell proliferation and colony forming capability of PCa cells. In addition, quantitative real-time polymerase chain reaction and Western blot analysis showed a significant decrease of KDM4A in response to miR-10a elevation in PCa cells. Using dual luciferase assay, we confirmed that KDM4A was a target gene for miR-10a. Furthermore, Western blot analysis indicated that miR-10a overexpression inactivated YAP signaling and suppressed transcription of YAP target genes. Additionally, cell growth arrest and colony forming capacity inhibition induced by miR-10a overexpression could be reversed by YAP overexpression in PCa cells. More importantly, miR-10a mimics inhibited PC-3 tumor growth in nude mice accompanied with a remarkable reduction of KDM4A and YAP expression. In conclusion, our results uncovered a tumor suppressor role of miR-10a in PCa via negative regulation of KDM4A and its downstream Hippo-YAP pathway.
miRNAs 的失调导致细胞异常生长，这在癌症中经常观察到。在本研究中，我们检测了 miR-10a 和赖氨酸特异性去甲基酶 4A（KDM4A）之间的表达和调控关系，以揭示它们在前列腺癌（PCa）进展中的作用。我们发现，与正常上皮细胞系 RWPE-1 相比，miR-10a 在 PCa 细胞系中的水平显著降低。与相邻正常组织相比，PCa 患者的肿瘤组织中也观察到 miR-10a 水平下调。miR-10a 水平的下调会促进 PCa 细胞的增殖和集落形成能力。此外，定量实时聚合酶链反应和 Western blot 分析显示，miR-10a 在 PCa 细胞中升高时，KDM4A 的表达显著下降。通过双荧光素酶报告基因实验，我们证实 KDM4A 是 miR-10a 的靶基因。此外，Western blot 分析表明，miR-10a 的过表达会使 YAP 信号失活，并抑制 YAP 靶基因的转录。此外，miR-10a 过表达诱导的细胞生长停滞和集落形成能力抑制可以通过 YAP 在 PCa 细胞中的过表达来逆转。更重要的是，miR-10a 模拟物抑制裸鼠 PC-3 肿瘤的生长，同时显著降低 KDM4A 和 YAP 的表达。总之，我们的研究结果揭示了 miR-10a 通过负调控 KDM4A 及其下游 Hippo-YAP 通路在 PCa 中的肿瘤抑制作用。
