ABSTRACT
Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non-small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to the upregulation of secreted protein, acidic and rich in cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates transforming growth factor beta (TGF-ß), extracellular signal-regulated kinase (ERK)1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-ß1 ligand and TGF-ß receptor 2 (TGF-ßR2) are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-ß1 and inhibition of TGF-ß1 mRNA expression modulates SPARC expression. Inhibition of MAP-ERK kinase (MEK) phosphorylation downregulates SPARC. MiR-29b is downregulated in Snail-overexpressing cell lines, whereas overexpression of miR-29b inhibits SPARC expression. In addition, miR-29b is upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-ß and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Osteonectin/metabolism , Transcription Factors/metabolism , Bronchi/cytology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Progression , Epithelial Cells/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic , Humans , Ligands , Lung Neoplasms/pathology , MicroRNAs/metabolism , Neoplasm Invasiveness , Phosphorylation , Prognosis , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Signal Transduction , Snail Family Transcription Factors , Transforming Growth Factor beta/metabolism , Up-RegulationABSTRACT
The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis. Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.
