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      Non-Random Integration of the HPV Genome in Cervical Cancer

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          Abstract

          HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs) are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240). We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular genes, by HPV integration remains an issue to be fully resolved.

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          Most cited references 42

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          MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.

          MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by targeting the mRNA of protein-coding genes for either cleavage or repression of translation. The roles of miRNAs in lineage determination and proliferation as well as the location of several miRNA genes at sites of translocation breakpoints or deletions has led to the speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. Here we show that the highly malignant human brain tumor, glioblastoma, strongly over-expresses a specific miRNA, miR-21. Our studies show markedly elevated miR-21 levels in human glioblastoma tumor tissues, early-passage glioblastoma cultures, and in six established glioblastoma cell lines (A172, U87, U373, LN229, LN428, and LN308) compared with nonneoplastic fetal and adult brain tissues and compared with cultured nonneoplastic glial cells. Knockdown of miR-21 in cultured glioblastoma cells triggers activation of caspases and leads to increased apoptotic cell death. Our data suggest that aberrantly expressed miR-21 may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.
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            MicroRNAs in cancer: small molecules with a huge impact.

             Carlo Croce,  V Iorio (2009)
            Every cellular process is likely to be regulated by microRNAs, and an aberrant microRNA expression signature is a hallmark of several diseases, including cancer. MicroRNA expression profiling has indeed provided evidence of the association of these tiny molecules with tumor development and progression. An increasing number of studies have then demonstrated that microRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. Here we review our current knowledge about the involvement of microRNAs in cancer and their potential as diagnostic, prognostic, and therapeutic tools.
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              Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells.

              Human papillomaviruses (HPVs) are involved in the pathogenesis of cancer of the cervix (CaCx). MicroRNA (miRNA) expression analysis using Ambion (Austin, TX, USA) arrays showed that three miRNAs were overexpressed and 24 underexpressed in cervical cell lines containing integrated HPV-16 DNA compared to the normal cervix. Furthermore, nine miRNAs were overexpressed and one underexpressed in integrated HPV-16 cell lines compared to the HPV-negative CaCx cell line C-33A. Based on microarray and/or quantitative real-time PCR and northern blot analyses, microRNA-218 (miR-218) was specifically underexpressed in HPV-positive cell lines, cervical lesions and cancer tissues containing HPV-16 DNA compared to both C-33A and the normal cervix. Expression of the E6 oncogene of high-risk HPV-16, but not that of low-risk HPV-6, reduced miR-218 expression, and conversely, RNA interference of E6/E7 oncogenes in an HPV-16-positive cell line increased miR-218 expression. We also demonstrate that the epithelial cell-specific marker LAMB3 is a target of miR-218. We also show that LAMB3 expression is increased in the presence of the HPV-16 E6 oncogene and this effect is mediated through miR-218. These findings may contribute to a better understanding of the molecular mechanisms involved in cervical carcinogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                27 June 2012
                : 7
                : 6
                Affiliations
                Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Jena, Jena, Germany
                Pontificia Universidad Catolica de Chile, Faculty of Medicine, Chile
                Author notes

                Conceived and designed the experiments: MS MD IR CD. Performed the experiments: MS LJ. Analyzed the data: MS MD. Contributed reagents/materials/analysis tools: LJ CD. Wrote the paper: MS MD.

                Article
                PONE-D-12-09523
                10.1371/journal.pone.0039632
                3384597
                22761851
                Schmitz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Medicine
                Clinical Genetics
                Chromosomal Disorders
                Epidemiology
                Cancer Epidemiology
                Infectious Diseases
                Sexually Transmitted Diseases
                Human Papillomavirus Infection
                Viral Diseases
                Human Papillomavirus Infection
                Obstetrics and Gynecology
                Female Genital Diseases
                Gynecologic Cancers
                Oncology
                Basic Cancer Research

                Uncategorized

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