Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance
| العنوان: | Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance |
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| المؤلفون: | Colin F. Chignell, Bhalchandra A. Diwan, Jiaqiang Huang, Yu-Ying He, Jingbo Pi, Michael P. Waalkes |
| المصدر: | Oncogene. 25:3680-3688 |
| بيانات النشر: | Springer Science and Business Media LLC, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Keratinocytes, Cancer Research, Tumor suppressor gene, Arsenites, Carcinogenicity Tests, Ultraviolet Rays, Mice, Nude, Apoptosis, Human skin, medicine.disease_cause, Malignant transformation, Mice, Genetics, medicine, Animals, Humans, PTEN, Molecular Biology, Protein kinase B, Cells, Cultured, Etoposide, biology, Keratin-13, PTEN Phosphohydrolase, Staurosporine, HaCaT, Cell Transformation, Neoplastic, medicine.anatomical_structure, Doxorubicin, Immunology, biology.protein, Cancer research, Keratins, sense organs, Carcinogenesis, Keratinocyte, Proto-Oncogene Proteins c-akt, Signal Transduction |
| الوصف: | Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVA-long-treated (24 J/cm(2) once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC(r)-nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::733f3f85c021275d36eb0dff4ca67ce5Test https://doi.org/10.1038/sj.onc.1209384Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....733f3f85c021275d36eb0dff4ca67ce5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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