Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression.

Martin, Alberto, 1974-; Salvador, Fernando; Moreno-Bueno, Gema; Floristán, Alfredo; Ruiz Herguido, Cristina; Cuevas, Eva P. Cuevas; Morales, Saleta; Santos, Vanessa Sonia; Csiszar, Katalin; Dubus, Pierre; Haigh, Jody J.; Bigas Salvans, Anna; Portillo, Francisco; Cano, Amparo

Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression.

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dc.contributor.author Martin, Alberto, 1974-ca
dc.contributor.author Salvador, Fernandoca
dc.contributor.author Moreno-Bueno, Gemaca
dc.contributor.author Floristán, Alfredoca
dc.contributor.author Ruiz Herguido, Cristinaca
dc.contributor.author Cuevas, Eva P. Cuevasca
dc.contributor.author Morales, Saletaca
dc.contributor.author Santos, Vanessa Soniaca
dc.contributor.author Csiszar, Katalinca
dc.contributor.author Dubus, Pierreca
dc.contributor.author Haigh, Jody J.ca
dc.contributor.author Bigas Salvans, Annaca
dc.contributor.author Portillo, Franciscoca
dc.contributor.author Cano, Amparoca
dc.date.accessioned 2015-06-23T09:17:15Z
dc.date.available 2016-04-30T02:00:04Z
dc.date.issued 2015
dc.description.abstract Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.ca
dc.description.sponsorship This work has been supported by grants from the Spanish Ministry of Economy and Innovation SAF2010-21143 (AC), SAF2010-20175 (GMB), SAF2013-44739-R (AC and FP) and CONSOLIDERINGENIO 2010 CSD2007-00017 (AC); the AICR (12-1057) (AC and AM), the Spanish Instituto de Salud Carlos III [(RETIC-RD12/0036/0007 (AC), RETICCRD12/0036/0054 (AB), PI13/00132 (GMB)], Comunidad de Madrid (S2010/BMD- 2303) (AC and GMB) and AECC-2011 (GMB). AM and EPC are founded by postdoctoral contracts from S2010/BMD-2303 and AICR grants, respectively; FS was founded by a Jae-pre contract from the CSIC; and SM and VS are founded by technician contracts from the RETIC-RD12/0036/0007 and AICR grants, respectively
dc.format.mimetype application/pdfca
dc.identifier.citation Martin A, Salvador F, Moreno-Bueno G, Floristán A, Ruiz-Herguido C, Cuevas EP. et al. Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression. EMBO J. 2015 Apr 15;34(8):1090-109. doi: 10.15252/embj.201489975ca
dc.identifier.doi http://dx.doi.org/10.15252/embj.201489975
dc.identifier.issn 0261-4189
dc.identifier.uri http://hdl.handle.net/10230/24559
dc.language.iso engca
dc.publisher EMBO Pressca
dc.relation.ispartof The EMBO Journal. 2015 Apr 15;34(8):1090-109.
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-21143
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-20175
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-44739
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/CSD2007-00017
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.other Pell--Tumorsca
dc.title Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression.ca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/acceptedVersionca

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