Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Δe13, in esophageal squamous cell carcinoma

Lysyl oxidase-like 2 (LOXL2) participates in every stage of cancer progression and promotes invasion and metastasis. In this study, we identified a novel alternative splicing isoform of LOXL2, namely LOXL2 Δe13, which lacked exon 13. Deletion of exon 13 caused an open reading frame shift and produced a truncated protein. LOXL2 Δe13 was expressed ubiquitously in cell lines and tissues and was mainly localized to the cytoplasm. Although it showed impaired deamination enzymatic activity compared with full-length LOXL2, LOXL2 Δe13 promoted the cell mobility and invasion of esophageal squamous cell carcinoma (ESCC) cells to greater degrees. In further research on the mechanisms, gene expression profiling and signaling pathway analysis revealed that LOXL2 Δe13 induced the expression of MAPK8 without affecting the FAK, AKT, and ERK signaling pathways. RNAi-mediated knockdown of MAPK8 could block the cell migration promoted by LOXL2De13, but it had little effect on that of full-length LOXL2. Our data suggest that LOXL2 Δe13 modulates the effects of cancer cell migration and invasion through a different mechanism from that of full-length LOXL2 and that it may play a very important role in tumor carcinogenesis and progression. Key words: LOXL2, ESCC, alternative splicing, deamination enzymatic activity, migration and invasion. La proteine LOXL2 (lysyl oxidase-like 2) participe a toutes les etapes de la progression du cancer et favorise l'invasion et la metastase. Dans cette etude, les auteurs ont identifie une nouvelle isoforme de LOXL2 epissee de maniere alternative, soit LOXL2 Δe13, qui est depourvue d'exon 13. La deletion de l'exon 13 causait un deplacement du cadre de lecture ouvert et produisait une proteine tronquee. LOXL2 Δe13 etait exprimee de fa^on ubiquiste dans les lignees cellulaires et les tissus, et elle etait principalement localisee dans le cytoplasme. Meme si elle presentait une activite de desaminase plus faible, LOXL 2Δe13 favorisait la mobilite cellulaire et l'invasion des cellules de carcinome squameux resophagien (ESCC) a un degre plus eleve. Une recherche plus approfondie portant sur le mecanisme, le profil d'expression genique et la signalisation a revele que LOXL2 Δe13 induisait l'expression de MAPK8 sans affecter les voies signaletiques de FAK, AKT et ERK. Le knockdown de MAPK8 par un pARNi pouvait bloquer la migration cellulaire induite par LOXL2 Δe13, mais il n'avait que peu d'effet sur celle induite par LOXL2 de pleine longueur. Ces donnees suggerent que LOXL2 Δe13 module la migration et l'invasion des cellules cancereuses par un mecanisme different de celui de LOXL2 de pleine longueur, et qu'elle pourrait jouer un role tres important dans la carcinogenese et la progression des tumeurs. [Traduit par la Redaction] Mots-cles: LOXL2, ESCC, epissage alternatif, activite de desaminase, migration et invasion.
Introduction The lysyl oxidase (LOX) family is composed of 5 members: LOX and lysyl oxidase-like 1-4 (LOXL 1-4). All of these are secreted, copper-dependent amine oxidases that catalyze the crosslinking [...]