Staurosporine-induced apoptosis of HPV positive and negative human cervical cancer cells from different points in the cell cycle.
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In the present study, we compare the sensitivity of CaSki and HeLa cells (HPV positive, wild-type p53) and C33A cells (HPV negative, mutated p53) to a protein kinase inhibitor, the staurosporine (ST). We show that ST can reversibly arrest the three cervical-derived cell lines, either in G1 or in G2/M. Beyond certain ST concentrations or/and over 24 h exposure, the cells underwent apoptosis. This process took place in G1 and G2/M for C33A and CaSki plus HeLa cell lines, respectively. By using an in vitro cell-free system, we demonstrated that cytoplasmic extracts from apoptotic cells were sufficient to induce hallmarks of programmed cell death on isolated nuclei. Moreover, we found that only G2/M cytoplasmic extracts from viable CaSki and HeLa cells supplemented with ST, triggered apoptosis while exclusively G1 cytoplasmic fractions from C33A cells were efficient. Our study describes a possible involvement of the HPV infection or/and p53 status in this different ST-induced apoptosis susceptibility. (+info)
High-risk but not low-risk HPV E2 proteins bind to the APC activators Cdh1 and Cdc20 and cause genomic instability.
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Human papillomaviruses (HPVs) from the high-risk group are associated with cervical cancer, in contrast to HPVs from the low-risk group which are associated with benign lesions of the genital tract. Here, we show that high-risk, but not low-risk HPV E2 proteins, promote a mitotic block, often followed by metaphase-specific apoptosis, and which is independent of the viral oncogenes E6 and E7. High-risk HPV E2-expressing cells also show polyploidy, chromosomal mis-segregation and centrosome amplification leading to genomic instability. We link these defects to a specific and unusually strong interaction between high-risk E2 and both Cdc20 and Cdh1, two activators of the Anaphase Promoting Complex (APC), abnormal localization of Cdh1, and accumulation of APC substrates like cyclin B, in vivo. The finding that high-risk, but not low-risk HPV E2 proteins, induce genomic instability, raises the intriguing possibility that E2 proteins play a role in the oncogenic potential of high-risk papillomaviruses. (+info)
Factors influencing subcellular localization of the human papillomavirus L2 minor structural protein.
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Two structural proteins form the capsids of papillomaviruses. The major structural protein L1 is the structural determinant of the capsids and is present in 360 copies arranged in 72 pentamers. The minor structural protein L2 is estimated to be present in twelve copies per capsid. Possible roles for L2 in interaction with cell surface receptors and in virion uptake have been suggested. As previously reported, L2 localizes in subnuclear domains identified as nuclear domain 10 (ND10). As it was demonstrated that L2 is able to recruit viral and cellular proteins to ND10, a possible role for L2 as a mediator in viral assembly has been proposed. In this study, we determined factors influencing the localization of L2 at ND10. Under conditions of moderate L2 expression level and in the absence of heterologous viral components, we observed that, in contrast to previous reports, L2 is mainly distributed homogeneously throughout the nucleus. L2, however, is recruited to ND10 at a higher expression level or in the presence of viral components derived from vaccinia virus or from Semliki Forest virus. We observed that translocation of L2 to ND10 is not a concentration-dependent accumulation but rather seems to be triggered by yet unidentified cellular factors. In contrast to HPV 11 and 16 L2, the HPV 18 L2 protein seems to require L1 for efficient nuclear accumulation. (+info)
Expression of the high-risk human papillomavirus type 18 and 45 E7 oncoproteins in cervical carcinoma biopsies.
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E7 proteins are major oncoproteins of high-risk human papillomaviruses (HPVs), which play a key role in cervical carcinogenesis. These proteins have been shown to immortalize primary human cells. Due to the absence of antibodies with suitable sensitivity and specificity, little is known about expression of the E7 oncoproteins in naturally infected tissues. Recently, high-level expression of the E7 protein of HPV-16, the most prevalent oncogenic HPV type, was demonstrated in cervical carcinomas by immunohistochemistry; however, approximately 15 additional high-risk HPV types are known to be associated with cervical carcinoma. It is unknown whether the E7 oncoproteins of HPV-18 and -45, the second and third most prevalent HPV types, are expressed in cervical cancers. Using antibodies against HPV-18 and -45 E7 proteins, it is shown here for the first time that the HPV-18 and -45 E7 proteins can be detected in cervical carcinoma biopsies. Together with anti-HPV-16 E7 antibodies, this could create the possibility of detecting E7 oncoproteins in approximately 80 % of all cervical cancers. (+info)
Human papillomavirus 16, 18, and 33 infections and risk of prostate cancer: a Nordic nested case-control study.
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Epidemiologic evidence of sexual history has emerged as a consistently found risk factor for prostate cancer. Some studies have reported an association between human papillomavirus (HPV) infections and prostate cancer. We did a nested case-control study within cohorts of more than 200,000 men enrolled in three Nordic biobanking projects. Follow-up using cancer registry linkages identified 804 prospectively occurring prostate cancer cases. Four control subjects per case were randomly selected from eligible sets of matched subjects that were alive and free of cancer at the time of diagnosis of the corresponding case and were matched to cases on biobank cohort, age (+/-2 years), county of residence, and date of blood sampling (+/-2 months in the Finnish and Swedish cohorts, +/-6 months in the Norwegian cohort). The serum samples were analyzed by standard ELISAs for the presence of immunoglobulin G antibodies against HPV types 16, 18, and 33. The joint HPV-16/HPV-18/HPV-33 seroprevalence in the joint cohort was 13.4% (107 of 799) among cases and 14.0% (363 of 2,596) among controls (odds ratio, 0.94; 95% confidence interval, 0.74-1.19). There were no noteworthy differences when the data were analyzed by different HPV type, country, or antibody levels. Our data do not support an association between serologic markers of HPV-16, HPV-18, and HPV-33 infections and risk of prostate cancer. (+info)
Clonal history of papillomavirus-induced dysplasia in the female lower genital tract.
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BACKGROUND: Dysplastic lesions of the vagina or the vulva often occur in women who have a previous history of cervical dysplasia. Most lesions in the female lower genital tract are induced by infections with high-risk oncogenic human papillomaviruses (HR-HPVs), including HPV16 and HPV18. HR-HPV genomes frequently integrate into host cell chromosomes at random sites. We analyzed viral integration sites in multiple metachronous lesions of the lower genital tract from women previously treated for HR-HPV-positive cervical dysplasia or cancer to determine whether the metachronous lesions emerged from a single common preexisting dysplastic cell clone or as consequence of independent HR-HPV infection events in the female lower genital tract. METHODS: From among 1500 patients with anogenital lesions, seven patients with high-grade vaginal or vulvar lesions and with a previous history of cervical disease (five with prior high-grade cervical dysplasia and two with a history of cervical cancer) were included in this study. Integration sites of HPV16 or HPV18 in vaginal or vulvar lesions were mapped by an adaptor ligation polymerase chain reaction (PCR) method. The sequence information was used to design an integrate-specific PCR assay that was applied to DNA extracted from archival paraffin-embedded material derived from biopsy samples of cervical lesions. RESULTS: Identical HPV DNA integration loci were found in vaginal or vulvar and cervical samples of all lesions available for four of the five patients with a prior history of high-grade cervical dysplasia and for both patients with a history of cervical cancer. CONCLUSIONS: These data indicate that high-grade dysplastic lesions in the female lower genital tract may emerge primarily as monoclonal lesions from a transformed cell population derived from the uterine cervix. (+info)
Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands.
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We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n=1467), adenocarcinoma in situ (ACIS) (n=61), adenocarcinoma (n=70), and squamous cell carcinoma (SCC) (n=83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (OR(MH) 15.0; 95% CI 8.6-26.1 and 21.8; 95% CI 11.9-39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (OR(MH) 6.6; 95% CI 2.8-16.0 and 9.4; 95% CI 2.8-31.2, respectively). For SCC, HPV16 prevalence was elevated (OR(MH) 7.0; 95% CI 3.9-12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (OR(MH) 4.3; 95% CI 1.6-11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma. (+info)
Vaccines for cervical cancer.
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The review focuses on current and future prevention of invasive cervical cancer (ICC), the second most common cancer among women worldwide. Implementation of population-based cytological screening programmes, using the 'Pap' smear to detect pre-cancerous lesions in the cervix, has resulted in substantial declines in mortality and morbidity from ICC in North America and some European countries. However, cases of, and deaths from, ICC continue to occur. Primary prevention of infection with high-risk human papillomavirus (HPV) types, the central causal factor of ICC, could further reduce incidence of and mortality from ICC. This is particularly the case in developing countries, which bear 80% of the burden of ICC, and where effective Pap screening programmes are extremely difficult to implement. Very promising results from several trials of synthetic HPV type-specific monovalent (HPV 16) and bivalent (HPV 16 and 18) vaccines have recently been published, showing high efficacy against type-specific persistent HPV infection and development of type-specific pre-cancerous lesions. Large-scale phase III trials of a number of such vaccine candidates are currently underway, and there is real hope that an effective vaccine capable of protecting against infection with HPV types 16 and 18 (which together account for approximately 70% of cervical cancer cases worldwide), and thereby of preventing development of a very significant proportion of cases of ICC, could be available within the next 2 years. (+info)