Crosstalk between Desmoglein 2 and Patched 1 accelerates chemical-induced skin tumorigenesis.

Abstract

Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs. Desmoglein 2 (Dsg2) is an adhesion protein that is upregulated in many cancers and overexpression of Dsg2 in the epidermis renders mice more susceptible to squamous-derived neoplasia. Here we examined a potential crosstalk between Dsg2 and Hh signaling in skin tumorigenesis. Our findings show that Dsg2 modulates Gli1 expression, in vitro and in vivo. Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway. Furthermore, in response to DMBA/TPA, the Dsg2/Ptc1+/lacZ mice developed squamous lessons earlier than the WT, Ptc1(+/lacZ), and Inv-Dsg2 littermates. Additionally, DMBA/TPA induced BCC formation in all mice harboring the Ptc1(+/lacZ) gene and the presence of Dsg2 in Dsg2/Ptc1(+/lacZ) mice doubled the BCC tumor burden. Reporter analysis revealed activation of the Hh pathway in the BCC tumors. However, in the SCCs we observed Hh activity only in the underlying dermis of the tumors. Furthermore, Dsg2/Ptc1(+/lacZ) mice demonstrated enhanced MEK/Erk1/2 activation within the tumors and expression of Shh in the dermis. In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.

• Authors: Donna M Brennan-Crispi, Claudia Hossain, Joya Sahu, Mary Brady, Natalia A Riobo, Mỹ G Mahoney
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 11 Pg. 8593-605 (Apr 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25871385 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Desmoglein 2
• Dsg2 protein, mouse
• Hedgehog Proteins
• Patched Receptors
• Patched-1 Receptor
• Ptch1 protein, mouse
• Receptors, Cell Surface
• 9,10-Dimethyl-1,2-benzanthracene
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Carcinoma in Situ (genetics, pathology)
• Carcinoma, Basal Cell (genetics, pathology)
• Carcinoma, Squamous Cell (chemically induced, genetics, pathology)
• Cell Division
• Cocarcinogenesis
• Dermis (metabolism, pathology)
• Desmoglein 2 (genetics, physiology)
• Epidermis (metabolism, pathology)
• Gene Knock-In Techniques
• Genes, Reporter
• Genetic Predisposition to Disease
• Genotype
• Hair Follicle (metabolism)
• Hedgehog Proteins (physiology)
• Hyperplasia
• Keratinocytes (metabolism)
• Mice
• Mice, Transgenic
• Papilloma (genetics, pathology)
• Patched Receptors
• Patched-1 Receptor
• Receptors, Cell Surface (genetics, physiology)
• Signal Transduction (physiology)
• Skin Neoplasms (chemically induced, genetics)
• Stromal Cells (pathology)
• Tetradecanoylphorbol Acetate
• Time Factors