Papillomavirus E2 protein induces expression of the matrix metalloproteinase-9 via the extracellular signal-regulated kinase/activator protein-1 signaling pathway (original) (raw)
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Experimental Dermatology, 2006
Human papillomaviruses (HPV) are small DNA viruses that induce a wide variety of hyperproliferative lesions in cutaneous and mucosal epithelia. It is proposed that HPV is involved in non-melanoma skin cancer development. We have previously shown that HPV8 transgenic mice spontaneously develop papillomatous skin tumors. Histology revealed epidermal hyperplasia, acanthosis and hypergranulosis and in some cases squamous cell carcinomas (SCC). Zymographic and immunoblot analysis of normal skin extracts identified increased amounts of matrix metalloproteinase (MMP)-9, MMP-13 and MT1-MMP in HPV8-positive mice compared with HPV8-negative animals. In situ gelatin zymography of tumor specimens displayed a strong proteolytic activity in papillomas, and SCC putatively attributed to the increased amounts of activated MMP-9 found in tissue extracts. In addition, immunoblot analysis revealed increased amounts of active MMP-13 and MT1-MMP in tumor extracts as compared with control extracts. Immunohistochemical stainings of SCC specimens depicted MMP-13 to be specifically expressed in stromal fibroblasts neighboring the tumor islands, whereas MT1-MMP was detected both in tumor cells and in stromal cells. Taken together, these results implicate a role for MMPs in the development of HPV8-induced cutaneous tumors.
Uterine cervical neoplasia is a major health problem, and can be a leading cause of death. There is strong evidence that human papillomavirus (HPV) is the principal etiological agent in cervical neoplasia. The objective of this study was to investigate the correlation between HPV-16 and matrix metalloproteinase-9 (MMP-9) and uterine cervical neoplasia. Twenty six formalin fixed, paraffin embedded specimens from patients with uterine cervical neoplasia from teaching laboratories in Baghdad city, were included in this study. In addition fifteen apparently normal cervical tissue blocks have been obtained from patients undergoing hysterectomies for sustained uterine bleeding used as control group. In situ hybridization analysis was performed with cDNA probes to HPV-16 and MMP-9. The expression of HPV-16 and MMP-9 in uterine cervical neoplasia cases in the present study was 50% and 61% respectively, but relationship was not found between expression of HPV-16 and MMP-9 and uterine cervical neoplasia. In conclusion, HPV-16 and MMP-9 may have an essential role in progression of uterine cervical neoplasia.
Acta Obstetricia et Gynecologica Scandinavica, 2010
Objective. The expression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and tissue inhibitors of matrix metalloproteinases 1 (TIMP-1) and 2 (TIMP-2) in vulvar intraepithelial neoplasia (VIN I-III) and in vulvar invasive carcinoma were evaluated. Design. A retrospective study. Setting. Oulu University Hospital, Finland. Sample. The study population consisted of 68 patients with vulvar neoplasia (13 VIN I, 5 VIN II, 6 VIN III and 44 squamous cell carcinomas). Methods. Paraffin-embedded tissue samples were examined by immunohistochemistry. Main outcome measures. MMP-2, MMP-9, TIMP-1 and TIMP-2 expression in VIN compared to vulvar carcinoma. Results. In VIN I-III MMP-2 expression was positive in 13%, MMP-9 in 13%, TIMP-1 in 50% and TIMP-2 in 17% of patients. The positive expressions in patients with vulvar carcinoma were 52% for MMP-2, 36% for MMP-9, 41% for TIMP-1 and 78% for TIMP-2. Conclusions. We conclude that over-expression of MMP-2, MMP-9 and TIMP-2 may be associated with the progression from VIN to invasive vulvar squamous cell carcinoma.
The human papillomavirus 16 E5 gene potentiates MmuPV1-Dependent pathogenesis
Virology, 2020
The papillomavirus E5 gene contributes to transformation and tumorigenesis; however, its exact function in these processes and viral pathogenesis is unclear. While E5 is present in high-risk mucosotropic HPVs that cause anogenital and head and neck cancers, it is absent in cutaneous HPVs and the recently discovered mouse papillomavirus (MmuPV1), which causes papillomas and squamous cell carcinomas of the skin and mucosal epithelia in laboratory mice. We infected K14E5 transgenic mice, which express the high-risk mucosotropic HPV16 E5 gene in stratified epithelia, with MmuPV1 to investigate the effects of E5 on papillomavirus-induced pathogenesis. Skin lesions in MmuPV1-infected K14E5 mice had earlier onset, higher incidence, and reduced frequency of spontaneous regression compared to those in non-transgenic mice. K14E5 mice were also more susceptible to cervicovaginal cancers when infected with MmuPV1 and treated with estrogen compared to nontransgenic mice. Our studies support the hypothesis that E5 contributes to papillomavirus-induced pathogenesis.
The Human Papillomavirus Type 8 E2 Protein Induces Skin Tumors in Transgenic Mice
Journal of Investigative Dermatology, 2008
Transgenic mice expressing early genes of the cutaneous human papillomavirus 8 (HPV8) spontaneously develop skin papillomas, epidermal dysplasia, and squamous cell carcinoma (6%). As the HPV8 protein E2 revealed transforming capacity in vitro, we generated three epidermal specific HPV8-E2-transgenic FVB/N mouse lines to dissect its role in tumor development. The rate of tumor formation in the three lines correlated with the different E2-mRNA levels. More than 60% of heterozygous line 2 mice, but none of the HPV8-negative littermates, spontaneously developed ulcerous lesions of the skin over an observation period of up to 144 weeks, beginning on average 74 ± 22 weeks after birth. Most lesions presented infundibular hyperplasia and acanthosis combined with low-grade dysplasia. Severe dysplasia of the epidermis occurred in 6%. Two carcinomas revealed a sharply demarcated spindle-cell component. Only 3 weeks after a single UV irradiation, 87% of heterozygous line 2 and 36% of line 35 mice developed skin tumors. A rapidly growing invasive tumor composed of spindle cells arose 10 weeks after irradiation of a line-35 animal. The histology of skin cancers in HPV8-E2 mice is reminiscent of a subset of highly aggressive squamous cell carcinoma in immunosuppressed transplant recipients with a massive spindle-cell component.
Journal of Virology, 2006
The cottontail rabbit papillomavirus (CRPV) a and b subtypes display a conserved E8 open reading frame encoding a 50-amino-acid hydrophobic protein, with structural similarities to the E5 transmembrane oncoprotein of genital human PVs (HPVs). CRPV E8 has been reported to play a role in papilloma growth but not to be essential in papilloma formation. Here we report that the knockout of E8 start codon almost prevented wart induction upon biobalistic inoculation of viral DNA onto rabbit skin. The scarce warts induced showed very slow growth, despite sustained expression of E6 and E7 oncogenes. This points to an essential role of E8 in disturbing epidermal homeostasis. Using a yeast two-hybrid screen, we found that E8 interacted with the zinc transporter ZnT1, protocadherin 1 (PCDH1), and AHNAK/desmoyokin, three proteins as yet unrelated to viral pathogenesis or cell transformation. HPV16 E5 also interacted with these proteins in two-hybrid assay. CRPV E8 mainly localized to the Golgi apparatus and the early endosomes of transfected keratinocytes and colocalized with ZnT1, PCDH1, and AHNAK. We showed that ZnT1 and PCDH1 formed a complex and that E8 disrupted this complex. CRPV E8, like HPV16 E5, increased epidermal growth factor (EGF)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and both the EGF-dependent and the EGF-independent activity of activating protein-1 (AP-1). Competition experiments with a nonfunctional truncated ZnT1 protein showed that E8-ZnT1 interaction was required for AP-1 activation. Our data identify CRPV E8 as a key player in papilloma induction and unravel novel cellular targets for inducing the proliferation of keratinocytes.
The American Journal of Pathology, 2000
Matrix metalloproteinase 9 (MMP-9 , also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter -galactosidase so that activation of the MMP-9 promoter would be indicated by -galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen , a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed -galactosidase. However , all invasive tumors had evidence of -galactosidase expression. In addition to the breast carcinomas , a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also -galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any -galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express -galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages , confirm-ing that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.
Cervical cancer (CC) is the second most frequent neoplasm around the world; and the second cause of death by cancer in Mexican women . It is known that cervical precursor lesions called Low grade Squamous Intraepithelial Lesions (LSIL) or High grade (HSIL) practically present the same risk factors as for CC, by instance the HPV persistent infection, smoking, oral contraceptives consumption, multiparity, etc [2,3].
Proceedings of The National Academy of Sciences, 1993
Certain "high-risk" anogenital human papillomaviruses (HPVs) have been associated with the majority of human cervical carcinomas. In these cancers, two papillomaviral genes, E6 and E7, are commonly expressed. In this study we provide evidence that expression of the E6 and E7 genes from the high-risk HPV-16 in the skin of transgenic mice potentiated the development of preneoplastic lesions, and a high percentage of these epidermal lesions subsequently developed into locally invasive cancers. High levels of E6/E7 expression were found in these tumors relative to the preneoplastic lesions, and expression was localized to the proliferating, poorly differentiated epidermal cells. Also, the p53 and Rb genes were found to be intact, not mutationally inactivated, in representative skin tumors. These findings demonstrate that the E6 and E7 genes from a papillomavirus etiologically associated with human cervical cancer can contribute to the development of epidermal cancers in an animal model.