MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease
MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease
复制标题
DOI：
10.1172/jci34922
复制
发表时间：
2008-11-01
影响因子：
15.9
通讯作者：
LaRusso, Nicholas
中科院分区：
文献类型：
--
作者：
Lee, Seung-Ok;Masyuk, Tatyana;LaRusso, Nicholas
由于细胞周期失调导致的胆管上皮细胞过度增殖是多囊肝病（PCLD）中囊肿发生的一个关键特征。最近的证据表明 microRNA (miRNA) 在多种生物过程中发挥着调节作用，包括细胞增殖。因此，我们假设 miRNA 可能参与细胞周期选定成分的调节，并可能有助于肝囊肿发生。我们发现，源自 PCK 大鼠（一种常染色体隐性遗传性多囊肾病 (ARPKD) 模型）的胆管细胞系 PCK-CCL 与正常大鼠胆管细胞 (NRC) 相比，显示出 miRNA 表达的整体变化。更具体的分析显示，PCK-CCL 细胞以及 PCK 大鼠和 PCLD 患者的肝组织中 1 种 miRNA（miR15a）水平降低。 miR15a 表达的减少与其靶标细胞周期调节因子细胞分裂周期 25A (Cdc25A) 的上调相关。 PCK-CCL 细胞中 miR15a 的过度表达降低了 Cdc25A 水平，抑制细胞增殖并减少囊肿生长。相反，NRC中miR15a的抑制加速细胞增殖、增加Cdc25A表达并促进囊肿生长。综上所述，这些结果表明，miR15a 的抑制通过 Cdc25A 的失调促进肝囊肿发生。
Hyperproliferation of bile duct epithehal cells due to cell-cycle dysregulation is a key feature of cystogenesis in polycystic liver diseases (PCLDs). Recent evidence suggests a regulatory role for microRNAs (miRNAs) in a variety of biological processes, including cell proliferation. We therefore hypothesized that miRNAs may be involved in the regulation of selected components of the cell cycle and might contribute to hepatic cystogenesis. We found that the cholangiocyte cell line PCK-CCL, which is derived from the PCK rat, a model of autosomal recessive polycystic kidney disease (ARPKD), displayed global changes in miRNA expression compared with normal rat cholangiocytes (NRCs). More specific analysis revealed decreased levels of 1 miRNA, miR15a, both in PCK-CCL cells and in liver tissue from PCK rats and patients with a PCLD. The decrease in miR15a expression was associated with upregulation of its target, the cell-cycle regulator cell division cycle 25A (Cdc25A). Overexpression of miR15a in PCK-CCL cells decreased Cdc25A levels, inhibited cell proliferation, and reduced cyst growth. In contrast, suppression of miRl5a in NRCs accelerated cell proliferation, increased Cdc25A expression, and promoted cyst growth. Taken together, these results suggest that suppression of miR15a contributes to hepatic cystogenesis through dystregulation of Cdc25A.