Exp Mol Med.  2017 Jun;49(6):e348. 10.1038/emm.2017.80.

Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity

• Chen Y
• Xu J
• Yang C
• Zhang H
• Wu F
• Chen J
• Li K
• Wang H
• Li Y
• Li Y
• Dai Z

• KMID: 2386968
• DOI: http://doi.org/10.1038/emm.2017.80

Abstract

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.

MeSH Terms

Alanine Transaminase
Alkaline Phosphatase
Animals
Aspartate Aminotransferases
Biomarkers
Blotting, Western
Cell Cycle
Cell Cycle Checkpoints
Cell Proliferation
Cyclin D3
Hepatocytes*
Hindlimb Suspension
In Vitro Techniques
Liver*
Proliferating Cell Nuclear Antigen
Rats*
Real-Time Polymerase Chain Reaction
Space Flight
Up-Regulation*
Weightlessness*
Alanine Transaminase
Alkaline Phosphatase
Aspartate Aminotransferases
Biomarkers
Cyclin D3
Proliferating Cell Nuclear Antigen