Crosstalk between Desmoglein 2 and Patched 1 accelerates chemical-induced skin tumorigenesis
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Donna M. Brennan-Crispi1,2,3, Claudia Hossain1, Joya Sahu1, Mary Brady1, Natalia A. Riobo2,3, Mỹ G. Mahoney1,2,3
1Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA
2Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
3Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
Mỹ G. Mahoney, e-mail: [email protected]
Natalia A. Riobo, e-mail: [email protected]
Keywords: Desmoglein 2, hedgehog signaling, Patched 1, basal cell carcinoma, squamous cell carcinoma
Received: February 04, 2015 Accepted: February 08, 2015 Published: March 24, 2015
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.
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