Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas

Goldberg, M.; Rummelt, C.; Laerm, A.; Helmbold, Peter; Holbach, Leonard M.; Ballhausen, Wolfgang G.

doi:10.1111/j.1365-2133.2006.07433.x

Cited by 30 publications

(17 citation statements)

References 17 publications

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“…Tumor DNA was extracted according to Goelz et al [8] from 10-15 μm-thick formalin-fixed, paraffin-embedded serial sections. A microdissection was performed using a surgical blade under microscopy.…”

Section: Dna Extractionmentioning

confidence: 99%

Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas

et al. 2008

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Methylation of normally unmethylated CpG-rich islands in or near the promoter region has been associated with transcriptional inactivation of tumor-suppressor and tumor-related genes in human cancers. However, so far, only a few studies have searched for DNA methylation in penile carcinoma (PC). On the other hand, human papillomavirus (HPV) has been reported to be associated with the pathogenesis of PC. To elucidate the methylation status of PC and HPV infection, the methylation status of eight genes (DAPK, FHIT, MGMT, p14, p16, RAR-beta, RASSF1A, and RUNX3), the incidences of the HPV status, and the expression of Fhit protein were examined in 25 PCs. The frequencies of methylation were: 28% for DAPK, 92% for FHIT, 20% for MGMT, 4% for p14, 24% for p16, 24% for RAR-beta, 12% for RASSF1A, and 44% for RUNX3. Negative expression of Fhit protein was observed in 22 of the 25 cancers (88%). Among those 22, 20 showed methylation of the FHIT gene. HPV-DNA was detected in three of the 25 cancers (12%). Methylation of FHIT gene was frequently found than HPV infection, therefore methylation of the FHIT gene is suggested to play an important role in the pathogenesis of penile squamous cell carcinoma.

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Section: Dna Extractionmentioning

confidence: 99%

Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas

et al. 2008

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“…Therefore, we asked whether decreased Msh2 expression seen in skin tissues of K14-Angptl2 Tg mice was due to oxidative stress and subsequent epigenetic modification of Msh2. To do so, we analyzed Msh2 promoter methylation using COBRA, which provides reliable quantitative results across several DNA methylation levels (17,(33)(34)(35). Analysis of restriction digestion patterns of genomic DNA isolated from skin tissues of K14-Angptl2 Tg mice indicated increased methylation frequency at the Msh2 promoter, relative to levels seen in wild-type mice (Fig.…”

Section: Increased Oxidative Stress Parallels Angptl2 Expression In Mmentioning

confidence: 99%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.

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“…FHIT was hypermethylated in 9 of 9 (100%) periorbital BCC samples studied, and 6 of 8 (75%) BCCs from other body regions [4]. Silencing of FHIT gene expression might contribute to the defective DNA damage response in BCC [4].…”

Section: Bccmentioning

confidence: 95%

“…In the United States, about 1 million BCC cases are diagnosed annually, representing approximately 75% of all skin cancers, and sun-exposed skin is primarily affected [4]. BCC penetrates aggressively into the skin, but metastasis is very rare.…”

Section: Bccmentioning

confidence: 99%

Aberrant DNA methylation in skin diseases

Sawalha

2009

Journal of Dermatological Science

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Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas

Abstract: We have identified epigenetic silencing of the FHIT tumour suppressor gene as a frequent inactivation mechanism which is likely to contribute to functional deficiencies in DNA damage response of BCCs.

Cited by 30 publications

References 17 publications

Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas

Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aberrant DNA methylation in skin diseases

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