ABSTRACT
The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factorα (TNFα) increased the level of vascular cell adhesion molecule1 (VCAM1) expression in a dosedependent manner. The nuclear factor-κB (NF-κB), extracellular signalregulated kinase (ERK) and cJun Nterminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM1 expression induced by TNFα at the mRNA and protein levels (P<0.05). TNFα augmented the activation of NFκB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NFκB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NFκB, ERK and JNK signaling pathways.
Subject(s)
Extracellular Signal-Regulated MAP Kinases/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Mesenchymal Stem Cells/metabolism , NF-kappa B/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Anthracenes/pharmacology , Biomarkers , Butadienes/pharmacology , Cell Adhesion , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Immunophenotyping , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Nitriles/pharmacology , Phosphorylation , Tumor Necrosis Factor-alpha/drug effects , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
BACKGROUND: Nestin is associated with neoplastic transformation. However, the mechanisms by which nestin contributes regarding invasion and malignancy of gastric adenocarcinoma (GAC) remain unknown. Recent studies have shown that the epithelial-mesenchymal transition (EMT) is important in invasion and migration of cancer cells. In the present study, we aimed to investigate the expression of nestin and its correlation with EMT-related proteins in GAC. MATERIALS AND METHODS: The expression of nestin and EMT-related proteins was examined in GAC specimens and cell lines by immunohistochemistry and Western blotting. Clinicopathological features and survival outcomes were retrospectively analyzed. RESULTS: Positive nestin immunostaining was most obviously detected in the cytoplasm, nucleus or both cytoplasm and nucleus of tumor cells in 19.2% (24/125) of GAC tissues, which was significantly higher than that in normal gastric mucosa tissues (1.7%, 1/60) (p=0.001). Nestin expression was closely related to several clinicopathological factors and EMT-related proteins (E-cadherin, vimentin and Snail) and displayed a poor prognosis. Interestingly, simultaneous cytoplasmic and nuclear nestin expression correlated with EMT-related proteins (E-cadherin, vimentin and Snail) (p<0.05) and lymph node metastasis (p=0.041) and a shorter survival time (p<0.05), but this was not the case with cytoplasmic or nuclear nestin expression. CONCLUSIONS: Nestin, particularly expression in both cytoplasm and nucleus, might be involved in regulating EMT and malignant progression in GAC, with potential as an unfavorable indicator in tumor diagnosis and a target for clinical therapy.
