Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity.
Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity.
复制标题
大鼠肝脏中 miR-223 的上调可抑制模拟微重力下肝细胞的增殖。
DOI：
10.1038/emm.2017.80
复制
发表时间：
2017-06-23
影响因子：
12.8
通讯作者：
Dai Z
中科院分区：
文献类型：
--
作者：
Chen Y;Xu J;Yang C;Zhang H;Wu F;Chen J;Li K;Wang H;Li Y;Li Y;Dai Z
长期的太空飞行会影响身体的许多器官系统，包括代谢功能障碍。近年来，大量证据表明，肝脏是航天飞行中的一个脆弱器官。然而，微重力下肝细胞增殖和细胞周期控制的变化在很大程度上仍未得到探索。在本研究中，我们首先证实，血清中的天冬氨酸氨基转移酶，丙氨酸氨基转移酶和碱性磷酸酶，肝功能的生化标志物，改变大鼠尾部悬吊（TS）条件下，模拟微重力，如以前的报告所示。接下来，我们证明了与对照组相比，在不同的TS时间点（TS为14、28和42天），通过Ki 67、PCNA和PH 3测定的细胞增殖活性显著降低。实时荧光定量PCR和Western blotting检测结果显示，TS组细胞周期调控因子Ccna 2、Ccnd 1、Cdk 1、Cdk 2和cyclin D3的表达均明显降低。随后的分析显示，模拟微重力下的异常肝细胞增殖抑制与肝脏中miR-223的上调相关。我们进一步发现miR-223抑制Hepa 1 -6细胞的增殖，并确定CDK 2和CUL 1为其直接靶点。另外，CDK 2和CUL 1的表达降低与体内外p27的水平呈负相关，这可能是抑制肝细胞增殖的原因。总的来说，这些数据表明miR-223的上调与肝细胞生长的抑制相关，并揭示了miR-223在模拟微重力下大鼠肝细胞增殖障碍和病理生理过程中的作用。
Long-term spaceflight affects numerous organ systems in the body, including metabolic dysfunction. Recently, ample evidence has demonstrated that the liver is a vulnerable organ during spaceflight. However, the changes in hepatocyte proliferation and cell cycle control under microgravity remain largely unexplored. In the present study, we first confirmed that the serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, biochemical markers of liver function, were altered in rats under tail suspension (TS) conditions to simulate microgravity, as shown in previous reports. Next, we demonstrated that the cell proliferation activity, determined by Ki67, PCNA and PH3, was significantly decreased at the different TS time points (TS for 14, 28 and 42 days) compared with that in the control group. Consistently, the positive cell cycle regulators Ccna2, Ccnd1, Cdk1, Cdk2 and cyclin D3 were also significantly decreased in the TS groups as shown by quantitative real-time PCR and western blotting analysis. Subsequent analysis revealed that the aberrant hepatocyte proliferation inhibition under simulated microgravity was associated with the upregulation of miR-223 in the liver. We further found that miR-223 inhibited the proliferation of Hepa1-6 cells and identified CDK2 and CUL1 as its direct targets. In addition, the decreased expression of CDK2 and CUL1 was negatively correlated with the level of p27 in vitro and in vivo, which may have been responsible for retarding hepatocyte proliferation. Collectively, these data indicate that upregulation of miR-223 was associated with the inhibition of liver cell growth and reveal the role of miR-223 in rat hepatocyte proliferation disorders and the pathophysiological process under simulated microgravity.
登录
查看更多内容
影响因子：
--
作者：
Hua HW;Jiang F;Huang Q;Liao Z;Ding G
通讯作者：
Ding G
DOI：
10.1016/j.bbamcr.2013.11.005
发表时间：
2014-02
影响因子：
5.1
作者：
Kotoshiba, Shuhei;Gopinathan, Lakshmi;Pfeiffenberger, Elisabeth;Rahim, Anisa;Vardy, Leah A.;Nakayama, Keiko;Nakayama, Keiichi I.;Kaldis, Philipp
通讯作者：
Kaldis, Philipp
影响因子：
5.2
作者：
Chen, Guangdi;Li, Gang
通讯作者：
Li, Gang
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
4.8
作者：
Mangala, Lingegowda S.;Zhang, Ye;Wu, Honglu
通讯作者：
Wu, Honglu