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Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway
- Source :
- Oncogene
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Skin Neoplasms
Receptor, ErbB-2
DMBA
medicine.disease_cause
Inbred C57BL
Transcriptome
Mice
0302 clinical medicine
ErbB-2
Mice, Knockout
integumentary system
DLX3
ErbB Receptors
Survival Rate
medicine.anatomical_structure
9,10-Dimethyl-1,2-benzanthracene
Aged
Animals
Carcinogens
Carcinoma, Squamous Cell
Disease Models, Animal
Female
Homeodomain Proteins
Humans
Mice, Inbred C57BL
Neoplasm Grading
Signal Transduction
Tetradecanoylphorbol Acetate
Transcription Factors
030220 oncology & carcinogenesis
Keratinocyte
Receptor
Knockout
Biology
Article
03 medical and health sciences
2-benzanthracene
Genetics
medicine
Molecular Biology
Transcription factor
Survival analysis
Animal
Carcinoma
Epithelium
10-Dimethyl-1
030104 developmental biology
Squamous Cell
Disease Models
Cancer research
Carcinogenesis
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....a040f1b1b91374dd74da86f576ebc18c