The transmembrane protein LRIG2 increases tumor progression in skin carcinogenesis.
Aged
Aged, 80 and over
Animals
Carcinogenesis
/ pathology
Cell Differentiation
Cell Line, Tumor
Disease Progression
Epidermis
/ pathology
ErbB Receptors
/ metabolism
Homeostasis
Humans
Hyperplasia
Inflammation
/ pathology
Membrane Glycoproteins
/ metabolism
Mice, Inbred C57BL
Phenotype
Protein Binding
Skin Neoplasms
/ metabolism
Tetradecanoylphorbol Acetate
Thrombospondins
/ metabolism
EGFR
ERBB receptors
LRIG2
mouse model
skin carcinogenesis
squamous cell carcinoma
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
09
04
2019
revised:
18
09
2019
accepted:
01
10
2019
pubmed:
4
10
2019
medline:
20
6
2020
entrez:
4
10
2019
Statut:
ppublish
Résumé
Over the last few decades, the number of cases of non-melanoma skin cancer (NMSC) has risen to over 3 million cases every year worldwide. Members of the ERBB receptor family are important regulators of skin development and homeostasis and, when dysregulated, contribute to skin pathogenesis. In this study, we investigated leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), a transmembrane protein involved in feedback loop regulation of the ERBB receptor family during NMSC. LRIG2 was identified to be up-regulated in various types of squamous cell carcinoma (SCC), but little is known about LRIG2 in cutaneous SCC (cSCC). To investigate the function of LRIG2 in cSCC in vivo, we generated a skin-specific LRIG2 overexpressing transgenic mouse line (LRIG2-TG) using the Tet-Off system. We employed the 7,12-dimethylbenz(a)anthracene/12-O-tetra-decanoylphorbol-13-acetate (DMBA/TPA) two-stage chemical carcinogenesis model and analyzed the skin during homeostasis and tumorigenesis. LRIG2-TG mice did not exhibit alterations in skin development or homeostasis but showed an interaction between LRIG2 and thrombospondin-1, which is often involved in angiogenesis and tumorigenesis. However, during carcinogenesis, transgenic animals showed significantly increased tumor progression and a more rapid development of cSCC. This was accompanied by changes in the ERBB system. After a single TPA application, inflammation of the epidermis was enhanced during LRIG2 overexpression. In human skin samples, LRIG2 expression was identified in the basal layer of the epidermis and in hair follicles of normal skin, but also in cSCC samples. In conclusion, epidermal LRIG2 excess is associated with activated EGFR/ERBB4-MAPK signaling and accelerated tumor progression in experimentally induced NMSC, suggesting LRIG2 as a potential oncoprotein in skin.
Identifiants
pubmed: 31580518
doi: 10.1002/1878-0261.12579
pmc: PMC6822252
doi:
Substances chimiques
LRIG2 protein, human
0
Membrane Glycoproteins
0
Thrombospondins
0
ErbB Receptors
EC 2.7.10.1
Tetradecanoylphorbol Acetate
NI40JAQ945
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2476-2492Informations de copyright
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
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