title: Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression.
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.
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Salvador
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain Fundación MD Anderson International Madrid, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Floristán
authors.affiliation: Institut Hospital del Mar d'Investigacions Médiques (IMIM), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ruiz-Herguido
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Eva P
authors.initials: EP
authors.lastname: Cuevas
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Saleta
authors.initials: S
authors.lastname: Morales
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Santos
authors.affiliation: John A Burns School of Medicine, University of Hawaii, Honolulu HI, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Csiszar
authors.affiliation: Histologie et pathologie moléculaire des tumeurs, Universitie Bordeaux, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Vic., Australia.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
authors.affiliation: Institut Hospital del Mar d'Investigacions Médiques (IMIM), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain fportillo@iib.uam.es acano@iib.uam.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Portillo
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain fportillo@iib.uam.es acano@iib.uam.es.
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human
keywords: Loxl2 mouse models; Notch1; epidermal differentiation; male sterility; squamous cell carcinoma