Disabled 2 (Dab2) Regulates Tumour Progression in Skin Squamous Cell Carcinoma

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.