Decreased expression of the CDK inhibitor p27Kip1 and increased oxidative DNA damage in the multistep process of cervical carcinogenesis

Sgambato, Alessandro; Zannoni, Gian Franco; Faraglia, Beatrice; Camerini, Andrea; Tarquini, Elisabetta; Spada, Daniele; Cittadini, Achille

doi:10.1016/j.ygyno.2003.12.008

Cited by 25 publications

(28 citation statements)

References 32 publications

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“…It is noteworthy that in a previous study in which we analyzed the same molecular markers in cervical tumorigenesis, we observed a more dramatic reduction of p27 Kip1 expression in cervical diseases than the one observed in vulvar lesions. 17 These findings support the hypothesis of a different molecular pathway for vulvar compared to cervical tumorigenesis and HPV might play a role in this phenomenon. In fact, HPV infection is present in the majority of cervical lesions 24 while it was never observed in our series of old patients with vulvar lesions.…”

Section: Discussionsupporting

confidence: 79%

“…19,20 p27 Kip1 is a negative regulator of cell-cycle progression acting as an inhibitor of cyclin/CDK complexes. 17 It has been implicated in negatively regulating cell proliferation in response to extracellular signals and is induced upon serum deprivation. In normal epithelial cells increased expression of p27 Kip1 mediates arrest of cells in the G1 phase of the cell cycle induced by different types of inhibitory signals.…”

Section: Discussionmentioning

confidence: 99%

“…7,21,22 It is of interest that loss of p27 Kip1 can be an early event in the multistep process of human tumorigenesis. 7,17 Progressive loss of p27 Kip1 is commonly observed during progression from normal to benign and malignant tumors, and its decreased expression has been related with the acquisition of a metastatic potential and a poorer prognosis. 7,21,22 Our results demonstrate that a decrease in p27 Kip1 expression is associated with the development of vulvar cancer and may play an important role in the early stage of vulvar tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…4.0, Media Cybernetic, Silver Spring, MA, USA), as previously reported. 17 All scoring and interpretations of the results were made by two of the authors independently (AS and GFZ) without knowledge of other clinicopathological variables. The few cases with discrepant scoring were re-evaluated jointly on a second occasion, and agreement was reached.…”

Section: Samplesmentioning

confidence: 99%

“…We also demonstrated that expression of p27 Kip1 is downregulated during cervical carcinogenesis and is inversely correlated with oxidative DNA damage. 15,17 Since the same risk factors (ie, cigarette smoke, HPV infection, sexual activity, etc) might be involved in the development of both cervical and vulvar cancers, in this study we investigated the role of these two markers in the less frequent vulvar carcinogenesis. The expression pattern of the p27 kip1 protein and of 8-OHdG was analyzed by immunostaining in vulvar normal epithelium and in different vulvar lesions including lichen sclerosus, squamous cell hyperplasia, VIN and invasive squamous cell carcinomas.…”

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confidence: 99%

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Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

et al. 2006

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Vulvar cancer represents an important medical problem worldwide whose incidence is increasing at an alarming rate in young females. Several factors have been linked to vulvar cancer development, but its exact pathogenesis remains to be determined. Vulvar tumorigenesis proceeds through intermediate dysplastic lesions, known as vulvar intraepithelial neoplasias, frequently associated with non-neoplastic epithelial disorders of the vulva, such as lichen sclerosus and squamous cell hyperplasia. In this study, the expression of the CDK inhibitor p27 Kip1 and the extent of endogenous oxidative DNA damage were evaluated in vulvar specimens, including normal tissues, lichen sclerosus, squamous cell hyperplasia, vulvar intraepithelial neoplasias and invasive squamous cell carcinomas. We found that p27 Kip1 was constantly expressed in normal vulvar epithelium cells while a progressive significant reduction in the percentage of p27 Kip1 -positive cells was observed in vulvar intraepithelial neoplasias (77%) and in invasive carcinomas (64%). Mean percentage of positive cells in invasive carcinomas, but not in vulvar intraepithelial neoplasias, was also significantly lower than squamous cell hyperplasia lesions (78%) while lichen sclerosus displayed a percentage of positive cells (45%) significantly lower than both vulvar intraepithelial neoplasias and invasive carcinomas. 8-hydroxydeoxyguanosine (8-OHdG) is considered a sensitive biomarker for oxidative stress. We observed a progressive significant increase in the levels of 8-OHdG and in the percentage of positive cells from normal vulvar epithelium to vulvar intraepithelial neoplasias (25%) and to invasive carcinomas (64%). Squamous cell hyperplasia displayed an intermediate percentage of positive cells comparable to vulvar intraepithelial neoplasias 2 but significantly higher than vulvar intraepithelial neoplasias 1 and lower than invasive carcinomas. Lichen sclerosus staining was significantly lower than carcinomas but higher than vulvar intraepithelial neoplasias and squamous cell hyperplasia. These results demonstrate that expression of p27 Kip1 is downregulated while oxidative DNA damage increases from early non-neoplastic epithelial alterations through vulvar intraepithelial neoplasias to invasive vulvar carcinomas. Thus, both parameters might play an important role in the development of this cancer and their study might contribute to our understanding of human vulvar carcinogenesis. Keywords: vulvar cancer; tumorigenesis; cell cycle; oxidative DNA damage Squamous cell carcinoma of the vulva accounts for 4% of all gynecologic malignancies and although its incidence rates in older women have remained relatively stable over the past few decades, diagnosed cases of vulvar cancer are increasing at an alarming rate in young females worldwide. 1 The type of vulvar squamous cell carcinoma usually found in younger women appears to be associated with human papillomavirus (HPV) infection. Indeed, specific genital HPV types, in particular HPV 16, are strongly implicated in the ...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Samplesmentioning

confidence: 99%

mentioning

confidence: 99%

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Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

et al. 2006

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Increased vascular endothelial growth factor expression, CD3‐positive cell infiltration, and oxidative stress in premalignant lesions of the cervix

Carrero

Callejas

Alaña

et al. 2009

Cancer

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BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in cervical intraepithelial neoplasia (CIN) progression. The occurrence of leukocytes has been documented in CIN; however, their role in VEGF production remains unknown. Oxidative stress has been involved in the progression of malignant neoplasias, but to the authors' knowledge tissue oxidative stress in CIN has not been documented. The objective of the current study was to investigate the expression of VEGF, leukocyte infiltration, leukocyte VEGF expression, and nitrogen/oxygen metabolism in cervical tissues from patients with CIN. METHODS: Indirect immunofluorescence was used to study the expression of VEGF and leukocyte infiltration in cervical samples from 55 patients with CIN and 7 normal controls. Superoxide anion (O2−) expression was determined by a cytochemical method, and tissue and serum nitric oxide by the Griess reaction. Human papillomavirus (HPV) DNA and HPV types were identified by the hybrid capture 2 HPV DNA test. RESULTS: Increased expression of VEGF was observed related to the progression of CIN. A significant increment of CD3 lymphocytes was found in CIN type 3 (CIN 3) and coexpression of CD3/VEGF and monocyte‐macrophage/VEGF in CIN 2 and 3. Increased O2−‐positive cells were found in CIN 2 and 3; however, tissue nitrate‐nitrite content remained similar to controls. The incidence of HPV infection was 16% in patients with CIN. No significant differences were observed in the values of HPV‐positive or HPV‐negative patients. CONCLUSIONS: Different factors leading to cervical neoplasia progression may be involved in the evolution of CIN, and the presence of these factors is most likely not related to the HPV infection status. Cancer 2009. © 2009 American Cancer Society.

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Human Papillomavirus-Related Cancers

Freitas

Gurgel

Chagas

et al. 2015

Infection and Cancer: Bi-Directorial Interactions

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Decreased expression of the CDK inhibitor p27Kip1 and increased oxidative DNA damage in the multistep process of cervical carcinogenesis

Cited by 25 publications

References 32 publications

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

Increased vascular endothelial growth factor expression, CD3‐positive cell infiltration, and oxidative stress in premalignant lesions of the cervix

Human Papillomavirus-Related Cancers

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