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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
Published on: December 19, 2019
Disabled 2 (Dab2) Regulates Tumour Progression in Skin Squamous Cell Carcinoma
Sayoni Roy1,2, Darshan Mehta1,2, Suruchi Sawant1
1Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Abstract:
Dab2 is an endocytic adaptor protein involved in various physiological processes and signaling pathways. Dab2 is deregulated in various cancers; however, its role in skin squamous cell carcinoma ( SCC) has not been elucidated yet. In the present study, we used the DMBA/TPA induced murine skin carcinogenesis model to examine the role of Dab2 in skin tumour progression. We generated tamoxifen inducible Dab2 conditional knockout system for our study. Loss of Dab2 led to delayed papilloma initiation and reduced papilloma burden. Delayed papilloma initiation was due to reduce proliferative potential of the papillomas due to Dab2 loss. Furthermore, while the WT papillomas progressed to SCC, the papillomas formed in Dab2 cKO mice failed to undergo malignant conversion to SCC. Dab2 cKO tumours showed reduced expression of K8, a marker for aggressive tumour. Moreover, Dab2 ckO tumours failed to undergo EMT as shown by reduced expression of Vimentin and Twist1. Dab2 cKO tumours also showed reduced expression of Sox2, a stem cell marker. Furthermore, qPCR analysis showed upregulation of Dab2 expression in the human skin cancer cell lines as compared to normal human skin keratinocytes. In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC.
Insights
Loss of Dab2 protein delayed skin tumor initiation and progression in mice. Dab2 loss prevented malignant conversion to squamous cell carcinoma (SCC), indicating Dab2 promotes skin cancer development.
Area of Science:
- Oncology
- Cell Biology
- Dermatology
Background:
- Dab2 (Disabled homolog 2) is an endocytic adaptor protein implicated in various cellular functions.
- Dab2 dysregulation is observed in several cancers, but its specific role in skin squamous cell carcinoma (SCC) remains unclear.
Purpose of the Study:
- To investigate the role of Dab2 in the initiation and progression of skin squamous cell carcinoma (SCC).
Main Methods:
- Utilized a DMBA/TPA-induced murine skin carcinogenesis model.
- Generated a tamoxifen-inducible Dab2 conditional knockout (cKO) system in mice.
- Analyzed tumor initiation, burden, proliferation, malignant conversion, and expression of key markers (K8, Vimentin, Twist1, Sox2).
- Examined Dab2 expression in human skin cancer cell lines and correlated Dab2 levels with patient survival data (TCGA SKCM).
Main Results:
- Loss of Dab2 significantly delayed papilloma initiation and reduced tumor burden.
- Dab2 deficiency impaired papilloma proliferative potential and prevented malignant conversion to SCC.
- Dab2-deficient tumors exhibited reduced expression of K8, Vimentin, Twist1, and Sox2, indicating suppressed aggressiveness, epithelial-mesenchymal transition (EMT), and stemness.
- Human skin cancer cell lines showed upregulated Dab2 expression compared to normal keratinocytes.
- TCGA data analysis revealed a trend where high Dab2 levels correlated with poorer overall survival in skin cancer patients.
Conclusions:
- Dab2 plays a crucial role in promoting skin squamous cell carcinoma (SCC) progression.
- Targeting Dab2 may represent a potential therapeutic strategy for skin cancer.
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