| First Author | Singh A | Year | 2016 |
| Journal | Carcinogenesis | Volume | 37 |
| Issue | 1 | Pages | 72-80 |
| PubMed ID | 26586792 | Mgi Jnum | J:230584 |
| Mgi Id | MGI:5763326 | Doi | 10.1093/carcin/bgv162 |
| Citation | Singh A, et al. (2016) Genetic deletion of TNFalpha inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas in PKCepsilon transgenic mice via inhibition of cell survival signals. Carcinogenesis 37(1):72-80 |
| abstractText | Protein kinase C epsilon (PKCepsilon), a Ca(2+)-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 PKCepsilon level dictates the susceptibility of PKCepsilon 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 PKCepsilon-mediated development of SCC, using either DMBA-TPA or UVR, indicated elevated release of cytokine TNFalpha. To determine whether TNFalpha is essential for the development of SCC in TG mice, we generated PKCepsilon transgenic mice/TNFalpha-knockout (TG/TNFalphaKO) by crossbreeding TNFalphaKO with TG mice. We now present that deletion of TNFalpha in TG mice inhibited the development of SCC either by repeated UVR exposures or by the DMBA-TPA protocol. TG mice deficient in TNFalpha elicited both increase in SCC latency and decrease in SCC incidence. Inhibition of UVR-induced SCC development in TG/TNFalphaKO was accompanied by inhibition of (i) the expression levels of TNFalpha 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 TNFalpha is linked to PKCepsilon-mediated sensitivity to DMBA-TPA or UVR-induced development of cutaneous SCC. |
