Romanian Academy Stefan S Nicolau Virology Institute

Mihai Bravu, Romania

Romanian Academy Stefan S Nicolau Virology Institute

Mihai Bravu, Romania
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Botezatu A.,Romanian Academy Stefan S Nicolau Virology Institute | Goia-Rusanu C.D.,Romanian Academy Stefan S Nicolau Virology Institute | Iancu I.V.,Romanian Academy Stefan S Nicolau Virology Institute | Huica I.,Romanian Academy Stefan S Nicolau Virology Institute | And 4 more authors.
Molecular Medicine Reports | Year: 2011

Cervical cancer is a leading cause of mortality in women. Molecular and epidemiological data have unequivocally confirmed that high-risk human papillomaviruses (HPVs) are a major etiological agent of this malignancy, as host epigenetic alterations are induced in response to viral infection. The present study evaluated the methylation status of CpG islands surrounding miR-124a, miR-34b and miR-203 in 29 cervical cancer precursor lesions, 31 cervical tumors and 30 normal control samples, with the aim of identifying potential markers of cervical cancer. Direct quantitative methylation-specific PCR (qMSP) was used to evaluate the degree of methylation in the samples. HPV DNA was detected and genotyped using the Linear Array HPV Genotyping Test. Data were statistically analyzed using the Kruskal-Wallis test. Differences in miRNA hypermethylation between the tumor and control samples were highly significant for all the genes tested (p<0.0001). Significant results were also obtained regarding the hypermethylation of miR-124a and miR-203 in the precursor lesions compared to the control samples. Among the 29 patients with precursor lesions, 68.97% (20/29) presented high risk (hr)-HPV genotypes and 31.03% (9/29) were diagnosed with low risk (Ir)-HPV. Significant results (p=0.0266) were obtained for miR-124a (hr-HPV group, mean 41.32; lr-HPV group, mean 6.74), revealing a strong association between the methylation process and the hr-HPV genotype. Borderline results (p=0.058) were obtained for miR-203 (hr-HPV group, mean 44.05; lr-HPV group, mean 3.33). These results confirm the involvement of epigenetic alterations in cervical oncogenesis. The lr-HPV precursor lesions had a methylation percent pattern similar to that of the normal samples, while the results for the hr-HPV precursor lesions and tumors indicate a possible involvement of the hr-HPV genotype in the miRNA methylation process.


Iancu I.V.,Romanian Academy Stefan S Nicolau Virology Institute
Roumanian archives of microbiology and immunology | Year: 2010

Human papillomaviruses (HPV) are considered the etiological agents of cervical cancer, especially high-risk genotypes. TGF-beta (transforming growth factor-beta) is well known for its anti-proliferative effects but the neoplastic cells often lose their sensitivity to TGF-beta. A characteristic alteration associated with malignant progression is the loss of responsiveness to TGF-beta1-induced cell growth inhibition. The aim of the present study was to establish the possible role of some members of TGF-beta signalling pathway during cervical cancer development and the possible relationship with HPV infection. In order to establish TGF-beta gene expression levels in cervical oncogenesis, TGF-beta1, TGF-beta1 receptors and Smad2 were investigated in precancerous and cervical cancer samples (Quantitative Real-Time PCR). The study revealed that 84.5% of patients were positive for HPV DNA. The most prevalent HPV genotypes were high-risk HPV 16 and 18 in single or co-infections. Expression of TGF-beta1 decreased as tumor cells progressed from cervical intraepithelial neoplasia to cervical carcinoma. Furthermore, we observed that cervical lesions without HPV infection expressed significantly less TGF-beta1. TGF-betaRI and Smad2 gene expression levels were found to be decreased in SCC and AC samples in contrast with CIN1 and CIN2/3 samples. Our results showed that in human cervical cancer the disruption of TGF-beta/Smad signalling pathway might contribute to the malignant progression of cervical dysplasia. These data emphasize the importance of canonical TGF-beta pathway integrity in carcinogenesis.


PubMed | Romanian Academy Stefan S Nicolau Virology Institute
Type: Journal Article | Journal: Roumanian archives of microbiology and immunology | Year: 2010

Cervical cancer remains one of the most important mortality causes worldwide. It is already known that high risk HPV (HR-HPV) has the main role in the development of pre- or cancerous lesions. Despite the fact that many studies focused on the HR-HPV viral loads as possible biomarkers, the viral load quantification utility for all HR-HPV genotypes is still a controversy. The purpose of our study was to determine if HPV16 and 18 viral load values might be a potential marker for HPV infection clearance versus of pre- and cancerous lesions development.80 women who tested positive for HPV16 and 18 were selected from a cohort of 250 patients. The samples, consisting in cervical smears, were collected in transport media ESwab (Copan). The patients average age was 36.26 years. HPV DNA detection, genotyping and viral load determination were performed twice for each patient (within one year follow-up).HPV 16 viral load was significantly higher in normal cytology samples and in HGSIL patients than in ASCUS/LGSIL (p value < 0.0312). HPV 18 viral load was also significantly higher in HGSIL cases than in ASCUS/LGSIL (p = 0,038). Independently of cervical cytology, HPV 18 viral load was lower (7.93 x 10(4) copies/microL) than HPV 16 viral load (5 x 10(13)) copies/microL).For HPV types 16 or 18 positive patients with LGSIL cytology the viral load might have predictive value. Our study suggested that patients with elevated viral loads are at disease risk progression and should be carefully evaluated.


PubMed | Romanian Academy Stefan S Nicolau Virology Institute
Type: Journal Article | Journal: Journal of cellular and molecular medicine | Year: 2013

The aim of this study was to investigate the role of methylenetetrahydrofolate reductase (MTHFR) polymorphisms and MTHFR methylation pattern in cervical lesions development among women from Romania, a country with high prevalence of human papillomavirus (HPV) cervical infections. To achieve this goal, blood samples and cervical cytology specimens (n=77)/tumour tissue specimens (n=23) were investigated. As control, blood and negative cytological smears (n=50) were used. A statistically significant association was found between T allele of C677T polymorphism and cervical lesions, heterozygote women presenting a threefold increased risk (normal/cervical lesions and tumours: wild homozygote 34/41 (0.68/0.41), heterozygote 14/51 (0.28/0.51), mutant homozygote 2/8 (0.04/0.08); OR=3.081, P=0.0035). Using square test for the control group, the HPV-negative and HPV-positive patients with cervix lesions, a significant correlation between viral infection and T allele of C677T polymorphism (P=0.0287) was found. The MTHFR promoter was methylated in all HGSIL and tumour samples, significant differences being noted between HPV-positive samples, control group and cases of cervical dysplastic lesions without HPV DNA (P<0. 0001) and between samples from patients with high-risk (hr)HPV versus low-risk (lr)HPV (P=0.0026). No correlations between polymorphisms and methylation were observed. In Romania, individuals carrying T allele are susceptible for cervical lesions. MTHFR promoter methylation is associated with cervical severity lesions and with hrHPV.


PubMed | Romanian Academy Stefan S Nicolau Virology Institute
Type: Journal Article | Journal: Roumanian archives of microbiology and immunology | Year: 2011

Human papillomaviruses (HPV) are considered the etiological agents of cervical cancer, especially high-risk genotypes. TGF-beta (transforming growth factor-beta) is well known for its anti-proliferative effects but the neoplastic cells often lose their sensitivity to TGF-beta. A characteristic alteration associated with malignant progression is the loss of responsiveness to TGF-beta1-induced cell growth inhibition. The aim of the present study was to establish the possible role of some members of TGF-beta signalling pathway during cervical cancer development and the possible relationship with HPV infection. In order to establish TGF-beta gene expression levels in cervical oncogenesis, TGF-beta1, TGF-beta1 receptors and Smad2 were investigated in precancerous and cervical cancer samples (Quantitative Real-Time PCR). The study revealed that 84.5% of patients were positive for HPV DNA. The most prevalent HPV genotypes were high-risk HPV 16 and 18 in single or co-infections. Expression of TGF-beta1 decreased as tumor cells progressed from cervical intraepithelial neoplasia to cervical carcinoma. Furthermore, we observed that cervical lesions without HPV infection expressed significantly less TGF-beta1. TGF-betaRI and Smad2 gene expression levels were found to be decreased in SCC and AC samples in contrast with CIN1 and CIN2/3 samples. Our results showed that in human cervical cancer the disruption of TGF-beta/Smad signalling pathway might contribute to the malignant progression of cervical dysplasia. These data emphasize the importance of canonical TGF-beta pathway integrity in carcinogenesis.

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