Mao Aihong, Liu Yang, Wang Yali, Zhao Qiuyue, Zhou Xin, Sun Chao, Di Cuixia, Si Jing, Gan Lu, Zhang Hong
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, People's Republic of China.
School of Nuclear Science and Technology, Lanzhou University, Lanzhou, 730000, People's Republic of China.
Tumour Biol. 2016 Apr;37(4):4831-40. doi: 10.1007/s13277-015-4336-8. Epub 2015 Oct 31.
miR-449a, a novel tumor suppressor, is deregulated in various malignancies, including prostate cancer. Overexpression of miR-449a induces cell cycle arrest, apoptosis, and senescence, but its role in response to ionizing radiation and underlying molecular mechanism are still unknown. Here, we report that miR-449a enhances radiation-induced G2/M phase arrest and apoptosis through modulating pRb/E2F1 and sensitizes prostate cancer cells to X-ray radiation. In wild-type Rb PC-3 cells, overexpression of miR-449a enhances radiation-induced G2/M arrest and apoptosis and promotes the sensitivity to X-ray radiation. While mutant Rb DU-145 cells are resistant to the X-ray radiation despite in the presence of miR-449a. The cell cycle distribution of DU-145 cells is not significantly altered by miR-449a in the response to ionizing radiation. Furthermore, elevated miR-449a downregulates cell cycle regulator CDC25A and oncogene HDAC1. By targeting genes involved in controlling pRb/E2F1 activity, miR-449a regulates cell cycle progression and apoptosis and consequently enhances the radiosensitivity of PC-3 cells. Thus, miR-449a, as a miRNA component of the Rb pathway, promotes the radiosensitivity of PC-3 cells through regulating pRb/E2F1.
miR-449a是一种新型肿瘤抑制因子，在包括前列腺癌在内的多种恶性肿瘤中表达失调。miR-449a的过表达可诱导细胞周期停滞、凋亡和衰老，但其在电离辐射反应中的作用及潜在分子机制仍不清楚。在此，我们报道miR-449a通过调节pRb/E2F1增强辐射诱导的G2/M期停滞和凋亡，并使前列腺癌细胞对X射线辐射敏感。在野生型Rb的PC-3细胞中，miR-449a的过表达增强辐射诱导的G2/M期停滞和凋亡，并提高对X射线辐射的敏感性。而突变型Rb的DU-145细胞尽管存在miR-449a，但对X射线辐射具有抗性。在对电离辐射的反应中，miR-449a对DU-145细胞的细胞周期分布没有显著影响。此外，miR-449a的升高下调细胞周期调节因子CDC25A和癌基因HDAC1。通过靶向参与控制pRb/E2F1活性的基因，miR-449a调节细胞周期进程和凋亡，从而增强PC-3细胞的放射敏感性。因此，miR-449a作为Rb通路的一个miRNA组分，通过调节pRb/E2F1促进PC-3细胞的放射敏感性。
