PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas.
Chronic exposure to UVR is the major etiologic factor in the development of human skin cancers including squamous-cell carcinoma (SCC). We have previously shown that protein Kinase C epsilon (PKCepsilon) transgenic mice on FVB/N background, which overexpress PKCepsilon protein approximately eightfold over endogenous levels in epidermis, exhibit about threefold more sensitivity than wild-type littermates to UVR-induced development of SCC. To determine whether it is PKCepsilon and not the mouse genetic background that determines susceptibility to UVR carcinogenesis, we cross-bred PKCepsilon FVB/N transgenic mice with SKH-1 hairless mice to generate PKCepsilon-overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCepsilon SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1-2 KJ m(-2)) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared with the wild-type hairless mice, PKCepsilon overexpression in SKH-1 hairless mice decreased the latency (12 weeks), whereas it increased the incidence (twofold) and multiplicity (fourfold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (proliferating cell nuclear antigen, signal transducers and activators of transcription 3, and extracellular signal-regulated kinase 1/2). The results indicate that PKCepsilon level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis.
Sand
Jordan M
JM
Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Aziz
Moammir H
MH
Dreckschmidt
Nancy E
NE
Havighurst
Thomas C
TC
Kim
KyungMann
K
Oberley
Terry D
TD
Verma
Ajit K
AK
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004817:Epidermis / Q000502:physiology / Q000528:radiation effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics*; D013045:Species Specificity; D014466:Ultraviolet Rays / Q000009:adverse effects*
D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases