Abstract
EMT (epithelial-mesenchymal transition) is crucial for cancer cells to acquire invasive phenotypes. In A549 lung adenocarcinoma cells, TGF-β elicited EMT in Smad-dependent manner and TNF-α accelerated this process, as confirmed by cell morphology, expression of EMT markers, capacity of gelatin lysis and cell invasion. TNF-α stimulated the phosphorylation of Smad2 linker region, and this effect was attenuated by inhibiting MEK or JNK pathway. Comprehensive expression analysis unraveled genes differentially regulated by TGF-β and TNF-α, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions. Integrated analysis of microRNA signature enabled us to identify a subset of genes, potentially regulated by microRNAs. Among them, we confirmed TGF-β-mediated induction of miR-23a in lung epithelial cell lines, target genes of which were further identified by gene expression profiling. Combined with in silico approaches, we determined HMGN2 as a downstream target of miR-23a. These findings provide a line of evidence that the effects of TGF-β and TNF-α were partially mediated by microRNAs, and shed light on the complexity of molecular events elicited by TGF-β and TNF-α.
Highlights
Lung cancer is the most frequent cancer type, which causes death of more than one million people every year
We have previously demonstrated that Transforming growth factor (TGF)-b induces Epithelial-mesenchymal transition (EMT) in A549 lung adenocarcinoma cells [16], which harbor an activating K-ras mutation and form a tumor with well-differentiated adenocarcinoma histology when subcutaneously injected into immunocompromized mice [17], [18]
First we characterized the effect of TGF-b and/or Tumor necrosis factor (TNF)-a on EMT in A549 lung cancer cells
Summary
Lung cancer is the most frequent cancer type, which causes death of more than one million people every year. Understanding of molecular events which govern invasive/metastatic spread of cancer cells is crucial for developing novel therapeutics of lung cancer. Epithelial-mesenchymal transition (EMT) is the differentiation switch directing epithelial cells to acquire mesenchymal phenotypes, which plays key roles during embryonic development as well as cancer invasion/metastasis. The hallmark of EMT is Ecadherin downregulation and subsequent loss of cell-cell adhesions, which is coupled with increased expression of mesenchymal markers including N-cadherin and vimentin. Transforming growth factor (TGF)-b plays a central role in the regulation of EMT and exhibits its pleiotropic effects through binding to receptors type I (TbR-I) and type II (TbR-II). TGF-b is often overexpressed in tumor tissues, and facilitates cancer progression through a diverse repertoire of tumor-cell-autonomous and host–tumor interactions, including enhancement of cell motility and invasion, which involves the process of EMT [5]
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