期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 135, 期 7, 页码 1882-1892出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2015.104
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资金
- Academy of Finland [137687, 138866]
- Academy of Finland (Centre of Excellence) [251314]
- Turku University Hospital [13336]
- Sigrid Juselius Foundation
- Cancer Research Foundation of Finland
- Centre for International Mobility
- Turku University Foundation
- Finnish Cultural Foundation
- Cancer Society of Finland
- Cancer Society of Southwestern Finland
- Orion-Farmos Research Foundation
- Maud Kuistila Foundation
- Academy of Finland (AKA) [138866, 137687, 138866, 137687] Funding Source: Academy of Finland (AKA)
Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer.
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