ABSTRACT
Bone marrow-derived mesenchymal stem cells (BMSCs) have therapeutic potential for certain heart diseases. Previous studies have shown that stem cells inhibit cardiac hypertrophy; however, it is necessary to explore the mechanisms underlying this effect. This study aimed to investigate the possible mechanism underlying the inhibitory effect of BMSCs on cardiomyocyte hypertrophy. We induced cardiomyocyte hypertrophy in cultured rat cells through isoproterenol (ISO) treatment with or without BMSC coculture. A microarray was performed to analyze messenger RNA expression in response to ISO treatment and BMSC coculture. Pathway enrichment analysis showed that the expression of differential genes was closely related to the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and that the expression of forkhead box O 1 (FoxO1) was significantly increased in the presence of BMSCs. Furthermore, we determined the expression levels of p-AMPK/AMPK and p-FoxO1/FoxO1 by western blot analysis. The expression of p-AMPK/AMPK was upregulated, whereas that of p-FoxO1/FoxO1 was downregulated upon coculturing with BMSCs. The AMPK-specific antagonist Compound C inhibited the downregulation of p-FoxO1/FoxO1 induced by the BMSC coculture. Furthermore, treatment with the specific FoxO1 antagonist AS1842856 reduced the inhibitory effects of BMSCs on cardiomyocyte hypertrophy in vivo and in vitro. Our present study demonstrates the inhibition of cardiomyocyte hypertrophy by BMSCs, which occurs partly through the AMPK-FoxO1 signaling pathway.
Subject(s)
Cardiomegaly/genetics , Mesenchymal Stem Cells/metabolism , Nerve Tissue Proteins/genetics , Transcription, Genetic , AMP-Activated Protein Kinases/metabolism , Animals , Cardiomegaly/pathology , Cell Membrane/drug effects , Cell Membrane/metabolism , Cell Proliferation/drug effects , Down-Regulation/drug effects , Gene Expression Profiling , Gene Ontology , Isoproterenol/pharmacology , Male , Mesenchymal Stem Cells/drug effects , Nerve Tissue Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Transcription, Genetic/drug effects , Up-Regulation/drug effectsABSTRACT
Irisin is a newly identified myokine that may be cancer-associated, and its impact on liver cancer is unclear. To understand the roles of irisin in liver cancer, we investigated its effect in HepG2 and SMCC7721 hepatocellular carcinoma cells, and the underlying mechanisms. We determined irisin levels in liver tissues and serum samples obtained from patients by using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Irisin levels in cancerous livers were significantly upregulated compared with those in control livers, but serum irisin levels remained unchanged. Additionally, we evaluated the effects of different concentrations of human recombinant modified and active (glycosylated) irisin (IM) or human recombinant nonmodified irisin (INM) on cell migration, proliferation, viability, and invasiveness. CCK8, transwell, and scratching assays demonstrated that irisin significantly increased cell proliferation, invasion, and migration through activation of the PI3K/AKT pathway. Irisin-induced cell proliferation, migration, and invasion were blocked by a PI3K inhibitor (LY294002). Irisin also decreased the cytotoxicity of doxorubicin in HepG2 cells. These data indicate that increased irisin levels may have protective roles in liver cancer cells through partial activation of the PI3K/AKT pathway, which may facilitate liver cancer progression and decrease the sensitivity to chemotherapy.
