Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas

Lysyl oxidase-like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically upregulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node-negative (N0) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways. ©2008 American Association for Cancer Research.
Grant support: Spanish Ministry of Education and Science SAF2004-00361, SAF2007-63051, NAN2004-09230-C04-02, Consolider-Ingenio2010-26102, and the EU MRTN-CT-2004-005428 (A. Cano), the Fundación Mutua Madrileña 2006 and the Spanish Ministry of Education and Science SAF2007-63075 (G. Moreno-Bueno), and the Scientific Foundation of AECC (H. Peinado and M. Mendiola). G. Moreno-Bueno is a junior research investigator ofthe Ramon y Cajal program 2004.