Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1
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Claudia Voena1,2,3,*, Lydia M. Varesio1,2,*, Liye Zhang4,*, Matteo Menotti1,2, Teresa Poggio1,2, Elena Panizza1,2, Qi Wang3, Valerio G. Minero1,2, Sharmila Fagoonee1,5, Mara Compagno1,2,3, Fiorella Altruda1,5, Stefano Monti4, Roberto Chiarle1,2,3
1Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
2Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy
3Department of Pathology, Children’s Hospital and Harvard Medical School, Boston, USA
4Section of Computational Biomedicine, Boston University School of Medicine, Boston, USA
5Molecular Biotechnology Center, University of Torino, Torino, Italy
*These authors have contributed equally to this work
Roberto Chiarle, e-mail: [email protected]
Keywords: lung cancer, ALK, EMT, ESRP1/2
Received: November 03, 2015 Accepted: March 29, 2016 Published: April 23, 2016
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.
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