Genetic deletion of TNF alpha inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas in PKC epsilon transgenic mice via inhibition of cell survival signals

摘要

Protein kinase C epsilon ( PKCe), a Ca2+- independent phospholipid- dependent serine/threonine kinase, is among the six PKC isoforms ( alpha, delta, epsilon, eta, mu, zeta) expressed in both mouse and human skin. Epidermal PKCe level dictates the susceptibility of PKCe transgenic ( TG) mice to the development of cutaneous squamous cell carcinomas ( SCC) elicited either by repeated exposure to ultraviolet radiation ( UVR) or by using the DMBA initiation- TPA ( 12- O- tetradecanoylphorbol- 13- acetate) tumor promotion protocol ( Wheeler, D. L. et al. ( 2004) Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation- induced cutaneous damage and development of squamous cell carcinomas. Cancer Res., 64, 7756- 7765). Histologically, SCC in TG mice, like human SCC, is poorly differentiated and metastatic. Our earlier studies to elucidate mechanisms of PKC epsilon- mediated development of SCC, using either DMBA- TPA or UVR, indicated elevated release of cytokine TNF alpha. To determine whether TNF alpha is essential for the development of SCC in TG mice, we generated PKC epsilon transgenic mice/ TNF alpha- knockout ( TG/ TNF alpha KO) by crossbreeding TNF alpha KO with TG mice. We now present that deletion of TNF alpha in TG mice inhibited the development of SCC either by repeated UVR exposures or by the DMBA- TPA protocol. TG mice deficient in TNFa elicited both increase in SCC latency and decrease in SCC incidence. Inhibition of UVR- induced SCC development in TG/ TNF alpha KO was accompanied by inhibition of ( i) the expression levels of TNF alpha receptors TNFRI and TNFRII and cell proliferation marker ornithine decarboxylase and metastatic markers MMP7 and MMP9, ( ii) the activation of transcription factors Stat3 and NF- kB and ( iii) proliferation of hair follicle stem cells and epidermal hyperplasia. The results presented here provide the first genetic evidence that TNF alpha is linked to PKC epsilon- mediated sensitivity to DMBA- TPA or UVR- induced development of cutaneous SCC.