Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin

Müller‐Decker, Karin; Reinerth, Günther; Krieg, Peter; Zimmermann, R.; Heise, H; Bayerl, Christiane; Marks, Friedrich; Fürstenberger, Gerhard

doi:10.1002/(sici)1097-0215(19990827)82:5<648::aid-ijc6>3.0.co;2-d

Cited by 106 publications

(101 citation statements)

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“…Permanent up-regulation of COX-2 already has been found in early stages of carcinogenesis and appears to be a consistent feature of neoplastic development in a wide variety of human and animal epithelia (10)(11)(12)(13). This holds true also for human squamous cell carcinogenesis, because aberrant COX-2 expression was found consistently in both preneoplastic cells of actinic keratoses and tumor cells of squamous cell carcinomas of skin (14). Using the experimental protocol of multistage carcinogenesis in mouse skin (9), we found aberrant COX-2 expression to be associated with the promotion stage (12,15), where initiated keratinocytes harboring a Ha-ras mutation clonally expand into preneoplastic papillomas, some of which subsequently develop into carcinomas.…”

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confidence: 64%

“…Using the experimental protocol of multistage carcinogenesis in mouse skin (9), we found aberrant COX-2 expression to be associated with the promotion stage (12,15), where initiated keratinocytes harboring a Ha-ras mutation clonally expand into preneoplastic papillomas, some of which subsequently develop into carcinomas. The close interrelation between COX-2 expression and inflammation (16), wounding (7), and skin carcinogenesis (14,15,17) prompted us to analyze the possible consequences of an aberrant overexpression of COX-2 in epidermal tissue in vivo.…”

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confidence: 99%

“…Total RNA was extracted from pulverized frozen tissues by using RNA Clean (AGS, Heidelberg, Germany), and RT-PCR was performed with the cDNA cycle kit (Invitrogen) as described (14). Using primers 5Ј-ATTCCTGCAGCCCAACATCTGT-3Ј and 5Ј-AGGTTCT-GCTTTGGGTTTGGG-3Ј ( Fig.…”

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Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin

Neufang

Fürstenberger

Heidt

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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In prostanoid biosynthesis, the first two steps are catalyzed by cyclooxygenases (COX). In mice and humans, deregulated expression of COX-2, but not of COX-1, is characteristic of epithelial tumors, including squamous cell carcinomas of skin. To explore the function of COX-2 in epidermis, a keratin 5 promoter was used to direct COX-2 expression to the basal cells of interfollicular epidermis and the pilosebaceous appendage of transgenic mouse skin. COX-2 overexpression in the expected locations, resulting in increased prostaglandin levels in epidermis and plasma, correlated with a pronounced skin phenotype. Heterozygous transgenic mice exhibited a reduced hair follicle density. Moreover, postnatally hair follicle morphogenesis and thinning of interfollicular dorsal epidermis were delayed. Adult transgenics showed a body-sitedependent sparse coat of greasy hair, the latter caused by sebaceous gland hyperplasia and increased epicutaneous sebum levels. In tail skin, hyperplasia of scale epidermis reflecting an increased number of viable and cornified cell layers was observed. Hyperplasia was a result of a disturbed program of epidermal differentiation rather than an increased proliferation rate, as reflected by the strong suppression of keratin 10, involucrin, and loricrin expression in suprabasal cells. Further pathological signs were loss of cell polarity, mainly of basal keratinocytes, epidermal invaginations into the dermis, and formation of horn perls. Invaginating hyperplastic lobes were surrounded by CD31-positive vessels. These results demonstrate a causal relationship between transgenic COX-2 expression in basal keratinocytes and epidermal hyperplasia as well as dysplastic features at discrete body sites.

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confidence: 64%

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Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin

Neufang

Fürstenberger

Heidt

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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186

154

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“…Immunoprecipitation of COX-2 and COX-1 as well as immunoblot analysis were carried out by using isoenzyme-specific antisera as described (6,10).…”

Section: Methodsmentioning

confidence: 99%

“…COX-2 was found to be overexpressed in premalignant actinic keratoses and papillomas as well as squamous cell carcinomas. This overexpression was observed in the tumor parenchyme (basal keratinocytes of papillomas and throughout the epithelium of actinic keratoses) and cells of the tumor stroma (6,(9)(10)(11). COX-2-selective inhibitors exhibited chemopreventive activity against chemically (6) and UV light-induced (11,12) skin carcinogenesis in mice.…”

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Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis

Müller‐Decker

Neufang

Berger

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Genetic and pharmacological evidence suggests that overexpression of cyclooxygenase-2 (COX-2) is critical for epithelial carcinogenesis and provides a major target for cancer chemoprevention by nonsteroidal antiinflammatory drugs. Transgenic mouse lines with keratin 5 promoter-driven COX-2 overexpression in basal epidermal cells exhibit a preneoplastic skin phenotype. As shown here, this phenotype depends on the level of COX-2 expression and COX-2-mediated prostaglandin accumulation. The transgenics did not develop skin tumors spontaneously but did so after a single application of an initiating dose of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Long-term treatment with the tumor promoter phorbol 12-myristate 13-acetate, as required for tumorigenesis in wild-type mice, was not necessary for transgenics. The ratios of squamous cell carcinomas to papillomas and of sebaceous gland adenomas to papillomas plus squamous cell carcinomas were increased markedly in transgenic mice treated with DMBA alone compared with DMBA͞phorbol 12-myristate 13-acetate-treated transgenic and wild-type mice. Thus, COX-2 overexpression, which leads to high levels of epidermal prostaglandin E 2, prostaglandin F2␣, and 15-deoxy ⌬12,14 -PGJ2, is insufficient for tumor induction but transforms epidermis into an ''autopromoted'' state, i.e., dramatically sensitizes the tissue for genotoxic carcinogens.

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Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: Evidence for growth suppression by inhibiting COX-2 expression

2000

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Cyclooxygenase (COX)‐2 is one of the rate‐limiting enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Recent studies have shown enhanced expression of COX‐2 in cancer cells of several tissues. We investigated the expression of COX‐2 and prostaglandin (PG) E 2 production in two human skin epidermal cancer cell lines: cutaneous squamous cell carcinoma, HSC‐5, and eccrine carcinoma, EcCa. Both COX‐2 expression and PGE 2 production were significantly enhanced in cancer cell lines compared with the non‐tumorigenic human keratinocyte cell line, HaCaT. In order to determine the role of COX‐2 in the proliferation of HSC‐5 and EcCa, the growth of untreated cells and cells transfected with COX‐2 antisense oligonucleotide was compared using the MTT assay. Transfection with the antisense oligonucleotide suppressed COX‐2 protein expression and significantly inhibited cell growth. The effect of a selective inhibitor of COX‐2, NS398, was compared with the effect of the antisense oligonucleotide in order to see whether COX‐2 expression and prostaglandins have selective effects on cell growth. COX‐2 expression was unchanged by NS398 treatment, whereas NS398 inhibited cell growth to a certain extent. The degree of growth inhibition was greater with the antisense oligonucleotide than with NS398. Our findings indicate that COX‐2 protein expression is enhanced in skin epidermal cancer cells and that COX‐2 plays a pivotal role in regulating cell growth. Furthermore, inhibition of COX‐2 expression had a more significant effect on growth suppression than inhibition of COX‐2 catalytic activity, suggesting the existence of two different signal pathways via COX‐2 in regulating cell growth. Int. J. Cancer 86:667–671, 2000. © 2000 Wiley‐Liss, Inc.

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Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin

Cited by 106 publications

References 19 publications

Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin

Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin

Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis

Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: Evidence for growth suppression by inhibiting COX-2 expression

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