Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin.
Expression of prostaglandin-H-synthase (PGHS) isozymes was analyzed in 50 biopsies of normal human skin and of pre-malignant and malignant skin lesions, by means of quantitative RT-PCR, immunoprecipitation and Western blotting, as well as immunohistochemistry. Normal skin constitutively expressed PGHS-1 in all cell layers of the epidermis, in endothelial cells of small blood vessels and in sweat-gland epithelium. PGHS-2 expression was very low and restricted to a few keratinocytes of the interfollicular and follicular epidermis. Steady-state concentrations of PGHS-1 and PGHS-2 mRNA were similar in normal skin and in basal-cell carcinomas, but PGHS-1 mRNA was reduced and PGHS-2 mRNA was elevated in actinic keratoses, squamous-cell carcinomas and keratoacanthomas. PGHS-1 protein was detected in all tumor biopsies, being occasionally increased in basal-cell carcinomas. High amounts of PGHS-2 protein were found in actinic keratoses, squamous-cell carcinomas and keratoacanthomas, but not in basal-cell carcinomas. Four malignant melanomas included in this study contained PGHS-1 but no PGHS-2 protein. Immunohistochemical analysis of the biopsies identified keratinocytes, in addition to cells of inflammatory infiltrates and of dendritic morphology, as the major PGHS-expressing cell types. PGHS-2-specific signals were spread throughout the epidermal part of actinic keratoses and squamous-cell carcinomas. These data suggest that constitutive up-regulation of PGHS-2 expression is a consistent pre-malignant event in squamous-cell cancer development in man, as it is in animal models of skin carcinogenesis. Thus, pre-cancerous lesions such as actinic keratoses present a likely target for chemoprevention of skin cancer by selective PGHS-2 inhibitors.
Research Program, Tumor Cell Regulation, Deutsches Krebsforschungszentrum, Heidelberg, Germany. K.Mueller-Decker@DKFZ-Heidelberg.de
K
K
Müller-Decker
G
G
Reinerth
P
P
Krieg
R
R
Zimmermann
H
H
Heise
C
C
Bayerl
F
F
Marks
G
G
Fürstenberger
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases