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EMBO J. 2015 Apr 15;34(8):1090-109. doi: 10.15252/embj.201489975. Epub 2015 Mar 10.

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

Author information

1
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain.
2
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain Fundación MD Anderson International Madrid, Madrid, Spain.
3
Institut Hospital del Mar d'Investigacions Médiques (IMIM), Barcelona, Spain.
4
John A Burns School of Medicine, University of Hawaii, Honolulu HI, USA.
5
Histologie et pathologie moléculaire des tumeurs, Universitie Bordeaux, Bordeaux, France.
6
Australian Centre for Blood Diseases, Monash University, Melbourne, Vic., Australia.
7
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, IdiPAZ, Madrid, Spain fportillo@iib.uam.es acano@iib.uam.es.

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.

KEYWORDS:

Loxl2 mouse models; Notch1; epidermal differentiation; male sterility; squamous cell carcinoma

PMID:
25759215
PMCID:
PMC4406654
DOI:
10.15252/embj.201489975
[Indexed for MEDLINE]
Free PMC Article

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