• Archives of Plastic Surgery
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• v.40 no.5
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• pp.517-521
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• 2013

Background Diabetes is characterized by chronic hyperglycemia, which can increase reactive oxygen species (ROS) production by the mitochondrial electron transport chain. The formation of ROS induces oxidative stress and activates oxidative damage-inducing genes in cells. No research has been published on oxidative damage-related extracellular superoxide dismutase (EC-SOD) protein levels in human diabetic skin. We investigated the expression of EC-SOD in diabetic skin compared with normal skin tissue in vivo. Methods The expression of EC-SOD protein was evaluated by western blotting in 6 diabetic skin tissue samples and 6 normal skin samples. Immunohistochemical staining was also carried out to confirm the EC-SOD expression level in the 6 diabetic skin tissue samples. Results The western blotting showed significantly lower EC-SOD protein expression in the diabetic skin tissue than in the normal tissue. Immunohistochemical examination of EC-SOD protein expression supported the western blotting analysis. Conclusions Diabetic skin tissues express a relatively small amount of EC-SOD protein and may not be protected against oxidative stress. We believe that EC-SOD is related to the altered metabolic state in diabetic skin, which elevates ROS production.

• Archives of Plastic Surgery
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• v.41 no.1
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• pp.35-39
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• 2014

Background Aurora kinase A (Aurora-A) plays an important role in the regulation of mitosis and cytokinesis. Dysregulated Aurora-A leads to mitotic faults and results in pathological conditions. No studies on Aurora-A expression in human diabetic skin tissue have been reported. In light of this, we explored the expression of Aurora-A in human diabetic skin tissue. Methods Aurora-A protein was evaluated by western blotting in 6 human diabetic skin tissue and 6 normal skin specimens. Results Increased expression of Aurora-A protein was detected in all diabetic skin tissue samples in both western blot analysis and immunohistochemical staining. However, in the case of the normal skin tissue, no bands of Aurora-A protein were detected in either the western blotting analysis or the immunohistochemical staining. Conclusions Thus far, there have been no studies on the expression of Aurora-A in diabetic skin tissue. However, we believe that oxidative DNA damage related to the expression of Aurora-A protein and Aurora-A could be involved inhuman diabetic skin tissue.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7439-7444
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• 2013

Aim: ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. Methods: In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Results: Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Conclusion: Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.

• Archives of Plastic Surgery
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• v.41 no.3
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• pp.248-252
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• 2014

Background Patients with diabetes mellitus often have a difficult life, suffering from foot ulceration or amputation. Diabetes is characterized by chronic inflammation, and one of the features of inflammation is hypoxia. Recently, it has been reported that KAI1 is a hypoxia target gene. There is no published research on hypoxia-related KAI1 protein levels in human diabetic skin. Therefore, we have investigated the expression of KAI1 protein in diabetic skin tissue in vivo. Methods The expression of KAI1 protein was evaluated by western blotting in 6 diabetic skin tissue samples and 6 normal skin samples. Immunohistochemical staining was carried out to identify KAI1 expression. Results The western blotting revealed significantly increased expression of the KAI1 protein in diabetic skin tissues as compared to normal skin tissues. Immunohistochemical examination demonstrated that KAI1 was expressed in all diabetic skin tissues with moderate-to-strong positivity and weakly expressed in normal skin tissues. Conclusions Our data suggest that a high expression of the KAI1 protein can be observed in diabetic skin tissue. To the best of our knowledge, this is the first report suggesting that KAI1 protein expression in diabetic skin tissues may be associated with chronic inflammatory states and hypoxia.

• Reproductive and Developmental Biology
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• v.30 no.4
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• pp.229-234
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• 2006

We have generated transgenic mice that expressed mouse extracellular superoxide dismutase (EC-SOD) in their skin. In particular, the expression plasmid DNA containing human keratin K14 promoter was used to direct the keratinocyte-specific transcription of the transgene. To compare intron-dependent and intron-independent gene expression, we constructed two vectors. The vector B, which contains the rabbit -globin intron 2, was not effective for mouse EC-SOD overexpression. The EC-SOD transcript was detected in the skin, as determined by Northern blot analysis. Furthermore, EC-SOD protein was detected in the skin tissue, as demonstrated by Western blot analysis. To evaluate the expression levels of EC-SOD in various tissues, we purified EC-SOD from the skin, lungs, brain, kidneys, livers, and spleen of transgenic mice and measured its activities. EC-SOD activities in the transgenic mice skin were approximately 7 fold higher than in wild-type mice. These results suggest that the mouse overexpressing vector not only induces keratinocyte-specific expression of EC-SOD, but also expresses successfully functional EC-SOD. Thus, these transgenic mice appeared to be useful for the expression of the EC-SOD gene and subsequent analysis of various skin changes, such as erythema, inflamation, photoaging, and skin tumors.

• Archives of Plastic Surgery
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• v.38 no.3
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• pp.217-221
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• 2011

Purpose: FGF4 (fibroblast growth factor 4) is a newly characterized gene which was found to be a transforming gene in several cancerous cells. FGF4 expression and amplification has been subsequently observed in several human cancers including stomach cancer, breast cancer, head and neck squamous cell carcinoma, lung cancer and bladder cancer. This study was designed to measure the protein expression of FGF4 in malignant skin cancers. Methods: We examined 8 normal skin tissues and 24 malignant skin tumor tissues which were 8 malignant melanomas, 8 squamous cell carcinomas and 8 basal cell carcinomas. The specimens were analyzed for the protein expression of FGF4 using immunohistochemical staining. To evaluate the amount of expression of FGF4, the histochemical score (HSCORE) was used. Results: FGF4 was expressed more intensely in malignant melanoma, followed by SCC and BCC in immunohistochemistry. The average HSCORE was 0.01 for normal skin, 2.02 for malignant melanoma, 1.28 for squamous cell carcinoma, and 0.27 for basal cell carcinoma, respectively. The expression of FGF4 in malignant melanoma and squamous cell carcinoma was increased in comparison with normal tissues and basal cell cancer, and the difference was statistically significant (p<0.05). The difference between malignant melanoma and squamous cell carcinoma was not statistically significant. Conclusion: These findings provide evidences that the expression of FGF4 plays an important role in malignant melanoma and squamous cell carcinoma progressions. This article demonstrates expression of FGF4 in human skin malignant tumors, and suggests that FGF4 is more expressed in highly aggressive skin tumors.

• Archives of Plastic Surgery
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• v.41 no.6
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• pp.654-660
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• 2014

Background Reactive oxygen species (ROS) damages cell molecules, and modifies cell signaling. The nuclear factor E2-related factor (Nrf2) is a critical transcription regulator, which protects cells against oxidative damage. Nrf2 expression is increased in a large number of cancers. However, little information has been reported regarding the expression of Nrf2 in skin cancers. Hence, we explored the expression of Nrf2 protein in skin cancers. Methods The Nrf2 protein expression in 24 specimens, including 6 malignant melanomas (MM), 6 squamous cell carcinomas (SCC), 6 basal cell carcinomas (BCC), and 6 normal skin tissues, was evaluated by western blotting. Immunohistochemical staining was performed. The expression of Kelch-like ECH-associated protein 1 (Keap1), the key regulator of Nrf2, was also analyzed by western blotting. Results Small interfering RNA transfection to the melanoma cell line G361 confirmed that an approximately 66 kDa band was the true Nrf2 band. The western blot revealed that the Nrf2 protein was definitely expressed in normal skin tissues, but the Nrf2 expression was decreased in MM, SCC, and BCC. Immunohistochemical examination showed that expression of Nrf2 was decreased in all skin cancer tissues compared to the normal skin tissues. Keap1 was not expressed in all malignant skin tumors and normal skin tissues by western blot. Conclusions ROS was increased in various types of cancers which proteins were highly expressed or underexpressed. This study demonstrated that the expression of Nrf2 protein was down-regulated in human malignant skin tumors. We suggest that decreased expression of Nrf2 is related to skin cancers.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.96-96
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• 2003

Previously, wogonin (5,7-dihydroxy-8-methoxyflavone) was found to suppress proinflammatory enzyme expression including cyclooxygenase-2 (COX-2), contributing to in vivo anti-inflammatory activity against skin inflammation. However, the detailed effect on each skin cell type has not been understood. Therefore, present investigation was carried out to find the effect of wogonin on inflammation-associated gene expression from skin fibroblasts in culture using reverse transcriptase-polymerase chain reaction. As a result, it was found that wogonin (10 - 100 ${\mu}$M) clearly down-regulated COX -2 expression from NIH/3T3 cells treated with 12-O-tetradecanoylphorbol 13-acetate, interleukin-1${\beta}$ or tumor necrosis factor-a. But, the expression levels of COX-1, interleukin-1${\beta}$ and fibronectin were not significantly affected. This finding was well correlated with significant reduction of prostaglandin E$_2$(PGE$_2$) production by wogonin. As a comparison, NS-398 (selective cyclooxygenase-2 inhibitor) did not suppress COX -2 expression and other gene levels, while PGE$_2$production was potently reduced at 0.1 - 10 ${\mu}$M. All these results suggest that COX -2 down-regulation of skin fibroblasts may be, at least in part, one of anti-inflammatory mechanisms of wogonin against skin inflammation.

• Nutritional Sciences
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• v.9 no.3
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• pp.212-226
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• 2006

The involvement of arachidonic acid (AA) metabolizing enzyme, lipoxygenase (LOX), in the development of particular tumors in humans has gradually been acknowledged and LOX has emerged as a novel target to prevent or treat human cancers. In the mouse skin carcinogenesis model, which provides an excellent model to study multistage nature of human cancer development, many studies have shown that some of the LOXs are constitutively upregulated in their expression. Moreover, application of LOX inhibitors effectively reduced tumor burdens, which implicates the involvement of LOX in mouse skin tumor development as well. 8S-LOX is a recently cloned LOX, which is specifically expressed in mouse skin after 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment but not in normal skin. Unlike other members of the LOX 'family' expressed in mouse skin, this TPA-induced expression of 8S-LOX is prominent only in the skin of the TPA tumor promotion-sensitive strains of mice (SENCAR, CD-1, and NMRI) but not in the promotion-resistant C57BL/6J mice. This is a very unique phenomenon among strains of mice. Constitutive upregulation of 8S-LOX was also found in early stage papillomas and the expression was gradually reduced as the tumors became malignant. Based on these observations, it has been thought that 8S-LOX is involved in TPA-induced tumor promotion as well as in tumor conversion from papillomas to carcinomas. In accordance with this hypothesis, several studies have suggested possible roles of 8S-hydroxyeicosatetraenoic acid (HETE), an AA metabolite of 8S-LOX, in mouse skin tumor development. A clastogenic activity of 8S-HETE was demonstrated in primary keratinocytes and a close correlation between the levels of etheno-DNA adducts and 8S-HETE during skin carcinogenesis was also reported. On the other hand, it has been reported that 8S-LOX protein expression is restricted to a differentiated keratinocyte compartment Moreover, reported findings on the ability of 8S-HETE to cause keratinocyte differentiation appear to be contrary to the procarcinogenic features of the 8S-LOX expression, presenting a question as to the role of 8S-LOX during mouse skin carcinogenesis. In this review, molecular and biological features of 8S-LOX as well as current views on the functional role of 8S-LOX/8S-HETE during mouse skin carcinogenesis are presented.

• Journal of Environmental Health Sciences
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• v.32 no.6
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• pp.566-570
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• 2006

Exposure to ultraviolet B(UVB) radiation causes skin inflammation such as pigmentation and the induction of cyclooxygenase-2(COX-2) gene expression. In this study, we investigated the effect of natural extracts from Tea, EGb 761 and Korean red ginseng(KRG), on the pigmentation and expression of COX-1 and COX-2 mRNA in UVB-irradiated C57BL/6 mice. Before UVB irradiation, the skin color was significantly showed the lightening effect by topical application of natural compounds (p<.05). In the case of UVB irradiated mice, we observed a decrease in pigmentation by compounds (p<.05). In irradiated skin, COX-1 mRNA expression is not changed following UVB irradiation, but COX-2 gene increases. Also, natural compounds lowered mRNA levels of COX-2. Therefore, these results suggest that COX-2 mRNA increases by UVB irradiation. Also, Tea, EGb 761 and KRG as a topical application may inhibit skin pigmentation and modulate COX-2 mRNA level.