Expression of Cyclin D1 and p53 Protein in Various Malignant Skin Tumors

Inohara, Shinichi; Kitagawa, Keiko; Kitano, Yukio

doi:10.1159/000246329

Cited by 28 publications

(18 citation statements)

References 11 publications

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“…Compared with normal skin, higher levels of cyclin D1 expression were found in all tumors of mouse [33]. Therefore, cyclin D 1 was considered a useful marker of some malignant skin tumors [12]. In our study, although more than half of all cases from the precursor lesions of dysplasia and carcinoma in situ.…”

Section: Discussionmentioning

confidence: 49%

Overexpression of cyclin D1 in nonmelanocytic skin cancer

et al. 2000

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Although the overexpression of cyclin D1 has been believed to play important roles in neoplastic transformation of some tumors, little is known about the function of cyclin D1 protein in carcinogenesis in human skin. A total of 307 patients with nonmelanocytic skin cancer, being 46 with Bowen's disease (BOD), 134 with squamous cell carcinoma (SCC) and 127 with basal cell carcinoma (BCC), were investigated immunohistochemically using monoclonal antibody to cyclin D1 by the LSAB method, to assess the expression of cyclin D1 in skin cancer including its precursors. The positive rates of cyclin D1 immunostaining in BOD, SCC and BCC were 63.0%, 69.4% and 54.3%, respectively. The positive rates in dysplasia adjoining BOD, SCC and BCC were 43.6%, 67.9% and 59.8%, respectively. In morphologically normal skin, however, only 2 cases, 1 of SCC and 1 of BCC, exhibited positive staining. These findings suggested that overexpression of cyclin D1 is an early event in dysplastic lesions of skin. Overexpression of cyclin D1 was related to sun exposure, especially in dysplasia of SCC. The score for cyclin D1 expression in dysplasia of BCC was correlated with age. Expression of cyclin D1 markedly increased from normal skin through dysplasia to BOD, but was not significantly related to the degree of SCC differentiation. These findings demonstrate that the effect of cyclin D1 overexpression is restricted to proliferation of cells, so that they gain a growth advantage, but their differentiation is not increased. Comparison with the results for p53 protein expression in these tumors, a significant correlation with cyclin D1 expression was found in dysplasia in BOD and SCC, and in patients with BCC who were less than 74 years old. These findings suggested the hypothesis that prior aberrant p53 expression may affect or regulate the overexpression of cyclin D1.

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Section: Discussionmentioning

confidence: 49%

Overexpression of cyclin D1 in nonmelanocytic skin cancer

et al. 2000

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“…Overexpression of cyclin D has also been observed in both human and mouse skin tumors (Inohara et al, 1996;Mitsunaga et al, 1995;Robles and Conti, 1995). Transgenic mice overexpressing cyclin D1 in the skin develop hyperplasia but no skin tumors (Robles et al, Figure 5 Normal p21 induction in transgenic keratinocytes following radiation.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of cyclin D has been observed in human SCCs and also in mouse skin tumors generated by a two-stage carcinogenesis proteocol (Inohara et al, 1996;Mitsunaga et al, 1995;Robles and Conti, 1995). No detectable expression of cyclin D (the antibody recognizes cyclins D1 and D2) was observed in non-tumor transgenic skin or in normal mouse skin (data not shown).…”

Section: High Proliferation Rate In Transgenic Skin and Tumorsmentioning

confidence: 91%

“…NF-kB has been shown to regulate the expression of several cell cycle proteins including p53, p21 Cip1/Waf and cyclin D (Bash et al, 1997;Hinz et al, 1999;Webster and Perkins, 1999). p53 mutations are frequently found in SCCs of the skin and cyclin D and p21 Cip1/Waf have been shown to be overexpressed in SCC (Ahmed et al, 1997;Inohara et al, 1996;Matsuta et al, 1997;Mitsunaga et al, 1995;Robles and Conti, 1995;Tron et al, 1996). To examine if expression of these proteins was altered in transgenic squamous cell carcinomas we used immunohistochemical analysis.…”

Section: High Proliferation Rate In Transgenic Skin and Tumorsmentioning

confidence: 99%

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Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

Hogerlinden

Auer²,

Toftgárd

2002

Oncogene

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In recent years a growth inhibitory role in skin for the Rel/NF-kB transcription factors has been established, and the block of Rel/NF-kB signaling results in rapid development of spontaneous skin cancer. The molecular mechanism underlying tumor development is however unknown. In the present study, we show that inhibition of NF-kB signaling in mouse skin by targeted expression of degradation resistant IkB-a generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by g-radiation. The results indicate that transgenic keratinocytes have a defect at the G1-S checkpoint whereas the G2-M checkpoint response was found to be intact. However, transgenic keratinocytes still respond by induction of the cyclin dependent kinase inhibitor p21 Cip1/Waf after exposure to g-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Haras or p53 gene, suggesting that inhibition of NF-kB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. These findings demonstrate an involvement of NF-kB signaling in the DNA damage response and cell cycle checkpoint control in the skin.

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“…66,67 Besides being a proliferation promoter, cyclin D1 can also act as a survival factor for tumor cells. [68][69][70] Here, we have shown a reduction in the percentage of cells positive for cyclin D1 in tumors from the Simva and LDE-PTX and Simva groups. In addition, in tumors from the Simva, LDE-PTX, and LDE-PTX and Simva …”

mentioning

confidence: 94%

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Kretzer¹,

Maria²,

Guido³

et al. 2016

IJN

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Purpose Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX.

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Expression of Cyclin D1 and p53 Protein in Various Malignant Skin Tumors

Cited by 28 publications

References 11 publications

Overexpression of cyclin D1 in nonmelanocytic skin cancer

Overexpression of cyclin D1 in nonmelanocytic skin cancer

Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

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