Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1

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.

Association of epithelial-to-mesenchymal transition circulating tumor cells in non-small cell lung cancer (NSCLC) molecular subgroups

“…All patients with ALK-rearrangements had higher proportion of vim+ CTCs in relation to total CTCs. However, no significant correlation with ALK-rearrangement and vimentin expression was observed which is in discordance with the data from other studies where EMT was associated with the response to treatment with ALK inhibitors (23,24). In the EGFR-assessed group, EGFR mutated patients had both significantly higher total CTC and vim+ CTC positivity than EGFR wt patients (P=0.038 and P=0.013, respectively).…”

Epithelial Splicing Regulatory Protein 1 Inhibits the Invasion and Metastasis of Lung Adenocarcinoma

“…EML4-ALK regulates EMT phenotype and represses ESRP1 in nonesmall cell lung carcinoma. 22 ESRP1 knockdown impaired E-cadherin up-regulation on ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These results indicated that ESRP1 is a key regulator of the EMT phenotype induced by oncogenic ALK in normal and cancer lung epithelial cells.…”

The RNA-binding protein ESRP1 promotes human colorectal cancer progression

“…The ESRP1 gene was also found to be the target of biallelic inactivating mutations in human colon cancers with microsatellite instability [13]. In agreement with the tumor suppressive role of ESRP1, several studies have shown that ESRP1 negatively regulates Epithelial-to-Mesenchymal Transition (EMT) in breast and pancreatic cancer, in oral squamous cell and non-small cell lung carcinomas [14,15,16,17]. Paradoxically, however, a pro-metastatic activity of ESRP1 has also been reported.…”