Keratinocyte Carcinoma

Albert, M. R.; Weinstock, Martin A.

doi:10.3322/canjclin.53.5.292

Cited by 76 publications

(68 citation statements)

References 49 publications

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“…The 1-kilowatt xenon arc lamp (XMN-1000-21; Optical Radiation Corp., Azuza, CA) irradiance was adjusted to 5 ϫ 10 Ϫ5 watts/cm 2 , and dishes were exposed to 15 mJ/cm 2 as measured with a research radiometer fitted with a UV light probe at 285 Ϯ 5 nm (model IL1700 A; International Light, Newburyport, MA) (56,57), a protocol that exposes cells to a spectrum of light resembling terrestrial sunlight (58). Shamirradiated cultures were handled identically, except that they were shielded with aluminum foil during irradiation.…”

Section: Methodsmentioning

confidence: 99%

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Marwaha

Chen

Helms

et al. 2005

Journal of Biological Chemistry

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Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UVirradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53 WT versus p53 DN ), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFB, a known positive regulator of COX-2 transcription. In p53 WT but not in p53 DN fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFB promoter-driven reporter plasmid and decreased NFB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.Nonmelanoma skin cancer accounts for well over 1 million cases of human malignancy annually in the United States, and the incidence continues to rise (1-3). The major initiator and promoter of skin cancer is UVB radiation (4, 5). Among the contributing effects of UVB radiation on skin are the formation of cyclobutane-pyrimidine dimers and pyrimidine (6-4) photoproducts (6, 7), which lead to mutations in key regulatory genes (8), epidermal hyperplasia (9, 10) allowing for expansion of mutated clones (11), immunosuppression (12, 13), and inflammation (14, 15).One way inflammation in particular is thought to affect carcinogenesis is by promoting epidermal hyperplasia and proliferation through production of cytokines and various second messengers such as prostaglandin E 2 (16). The major enzyme responsible for the UVB-induced prostaglandin synthesis is cyclooxygenase-2 (COX-2), 5 the inducible isoform of the cyclooxygenase enzyme (17) that carries out the ratelimiting step of prostaglandin and thromboxane production (18 -20). COX-2 has been shown to be overexpressed in numerous human malignancies, including colon, lung, and breast cancers (21-24). In relation to skin cancer, UVB irradiation increas...

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Section: Methodsmentioning

confidence: 99%

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Marwaha

Chen

Helms

et al. 2005

Journal of Biological Chemistry

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“…4 Approximately 8700 people are expected to die from melanoma in the United States during 2010, accounting for 65% of all skin cancer deaths. 3,5 The importance of diagnosing melanoma early in its evolution cannot be overstated. Because prognosis in melanoma is directly proportionate to the depth of the neoplasm, detection of melanoma early in its evolution is of crucial importance in saving lives.…”

Section: Introductionmentioning

confidence: 99%

The Evolution of Melanoma Diagnosis: 25 Years Beyond the ABCDs

Rigel

Russak

Friedman

2010

CA: A Cancer Journal for Clinicians

342

274

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Early detection of malignant melanoma remains the key factor in lowering mortality from this cancer. Recognizing the importance of this issue 25 years ago, our group at New York University published in CA: A Cancer Journal for Clinicians the mnemonic "ABCD" to facilitate the early diagnosis of melanoma. Studies have demonstrated the usefulness of this paradigm in enhancing early melanoma diagnosis as a part of clinical examinations, mass screenings, and public education programs. Approaches to melanoma diagnosis have dynamically evolved during the ensuing quarter century. In the 1990s, dermoscopy enabled the recognition of new subsurface features to differentiate between malignant and benign pigmented lesions. During the last decade, new computer-based technologies have improved diagnostic sensitivity and specificity and may result in optimizing lesion selection for biopsy and pathology review. Despite all of the advances in melanoma diagnosis, timely recognition, detection, and rapid treatment of melanoma remain critical. Although pathologic examination remains the gold standard for diagnosis, this cancer has the potential to be diagnosed through noninvasive approaches because of its cutaneous location. From the development of the ABCDs through current attempts that use complex computer algorithms and genetic markers, a clinician's ability to detect melanoma in its earliest form has been augmented. However, a "good clinical eye" is still fundamental to selecting the lesions for evaluation among the sea of those that are prevalent. As current approaches are refined and new techniques are developed, the improved ability to diagnose this cancer will hopefully enhance reaching the goal of reducing melanoma mortality. CA Cancer J Clin 2010;60:301-316.

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“…The skin provides an intensely studied model of selfrenewing epithelial tissues, with distinct stem cell populations giving rise to tumors with different behavior (1). Among these, skin squamous cell carcinomas (SCCs) are among the most frequent human cancers (2,3). Several genetic events have been implicated in the development and progression of this disease, including mutations and/or downmodulation of the tumor suppressor p53 (4,5), upregulation of its homolog p63 (6), and amplification and/or overexpression of the gene for EGFR (7,8).…”

Section: Introductionmentioning

confidence: 99%

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans

Mandinova¹,

Kolev²,

Neel³

et al. 2009

J. Clin. Invest.

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Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.

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Keratinocyte Carcinoma

Cited by 76 publications

References 49 publications

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

The Evolution of Melanoma Diagnosis: 25 Years Beyond the ABCDs

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans

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