Abstract
A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK-rearranged NSCLC are typically adenocarcinoma characterized by a solid signet-ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangement to an epithelial-mesenchymal transition (EMT) phenotype in NSCLC, but the extent and the mechanisms of an ALK-mediated EMT in ALK-rearranged NSCLC are largely unknown. We found that the ALK-rearranged H2228 and DFCI032, but not the H3122, cell lines displayed a mesenchymal phenotype. In these cell lines, oncogenic ALK activity dictated an EMT phenotype by directly suppressing E-cadherin and up-regulating vimentin expression, as well as expression of other genes involved in EMT. We found that the epithelial splicing regulatory protein 1 (ESRP1), a key regulator of the splicing switch during EMT, was repressed by EML4-ALK activity. The treatment of NSCLC cells with ALK tyrosine kinase inhibitors (TKIs) led to up-regulation of ESRP1 and E-cadherin, thus reverting the phenotype from mesenchymal to epithelial (MET). Consistently, ESRP1 knock-down impaired E-cadherin up-regulation upon ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These findings demonstrate an ALK oncogenic activity in the regulation of an EMT phenotype in a subset of NSCLC with potential implications for the biology of ALK-rearranged NSCLC in terms of metastatic propensity and resistance to therapy.
Keywords:
ALK; EMT; ESRP1/2; lung cancer.
MeSH terms
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Anaplastic Lymphoma Kinase
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Animals
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Antigens, CD
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Antineoplastic Agents / pharmacology
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Cadherins / genetics
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Cadherins / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / enzymology*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Down-Regulation
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Epithelial-Mesenchymal Transition* / drug effects
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Gene Expression Regulation, Neoplastic
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Mice, Inbred NOD
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Mice, SCID
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Phenotype
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism
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Signal Transduction
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Time Factors
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Transfection
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Vimentin / genetics
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Vimentin / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antigens, CD
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Antineoplastic Agents
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Biomarkers, Tumor
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CDH1 protein, human
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Cadherins
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Cell Cycle Proteins
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ESRP1 protein, human
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Microtubule-Associated Proteins
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Protein Kinase Inhibitors
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RNA-Binding Proteins
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Vimentin
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases
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EML4 protein, human
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Serine Endopeptidases