Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.
9,10-Dimethyl-1,2-benzanthracene
/ toxicity
Aged
Animals
Carcinogens
/ toxicity
Carcinoma, Squamous Cell
/ chemically induced
Disease Models, Animal
ErbB Receptors
/ genetics
Female
Homeodomain Proteins
/ genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Grading
Receptor, ErbB-2
/ genetics
Signal Transduction
Skin Neoplasms
/ chemically induced
Survival Rate
Tetradecanoylphorbol Acetate
/ toxicity
Transcription Factors
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
02
12
2020
accepted:
14
04
2021
revised:
30
03
2021
pubmed:
6
5
2021
medline:
22
1
2022
entrez:
5
5
2021
Statut:
ppublish
Résumé
Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is disrupted in the pathological development of cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. To investigate the impact of DLX3 expression on cSCC prognosis, we carried out clinicopathologic analysis of DLX3 expression which showed statistical correlation between tumors of higher pathologic grade and levels of DLX3 protein expression. Further, Kaplan-Meier survival curve analysis demonstrated that low DLX3 expression correlated with poor patient survival. To model the function of Dlx3 in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on mice genetically depleted of Dlx3 in skin epithelium (Dlx3cKO). Dlx3cKO mice developed significantly more tumors, with more rapid tumorigenesis compared to control mice. In Dlx3cKO mice treated only with DMBA, tumors developed after ~16 weeks suggesting that loss of Dlx3 has a tumor promoting effect. Whole transcriptome analysis of tumor and skin tissue from our mouse model revealed spontaneous activation of the EGFR-ERBB2 pathway in the absence of Dlx3. Together, our findings from human and mouse model system support a tumor suppressive function for DLX3 in skin and underscore the efficacy of therapeutic approaches that target EGFR-ERBB2 pathway.
Identifiants
pubmed: 33947961
doi: 10.1038/s41388-021-01802-9
pii: 10.1038/s41388-021-01802-9
pmc: PMC8159909
mid: NIHMS1694241
doi:
Substances chimiques
Carcinogens
0
Distal-less homeobox proteins
0
Homeodomain Proteins
0
Transcription Factors
0
9,10-Dimethyl-1,2-benzanthracene
57-97-6
EGFR protein, human
EC 2.7.10.1
ERBB2 protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Tetradecanoylphorbol Acetate
NI40JAQ945
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3680-3694Subventions
Organisme : Intramural NIH HHS
ID : Z01 AR041124
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AR041124
Pays : United States
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