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Richland County Democratic Executive Committee

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Logan Ideas
Logan Ideas

Under E6


However, the actual physical status of HPV 16 genome in cervical cancer cells appears far more complicated. For instance, Li et al. [4] reported the existence of HPV 16 integration in all of 15 cases of cervical cancer tissues, but Dutta S et al. [5] detected 82% cases contained HPV16 integrant in cervical cancer samples, and Mazumder D and his collogues found that 70.3% samples harbored integration HPV16 in cervical cancer tissue [6]. Further, Vinokurova and collaborators found that as high as 45% samples contained purely episomal virus in HPV16-positive cervical cancer tissues [7], and Cheung et al. [8] found pure episomal HPV16 genomes in 14 of 29 (48.3%) cervical cancer tissues. Therefore, HR-HPV genome indeed exists as episome except for integrant. This phenomenon points toward the biological plausibility of cervical carcinogenesis under the impact of HPV16 episome, in addition to E2 disruption due to viral genome integration into the host genome. It may be alternative mechanisms in episome-associated carcinogenesis, although, by which HPV 16 episome induces cervical carcinogenesis is unclear now.




under e6



Here, we detected HPV16 physical status, E6 mRNA transcript level, viral load, and E6 promoter methylation in HPV16 positive invasive cervical cancer tissues, and analyzed the association of HPV16 E6 expression with viral load and promoter methylation. The aim of the study was to understand the potential mechanism in cervical cancer pathogenesis with HPV16 episome infection.


E6 mRNA transcript expression was quantified by using the same primer. Human Endogenous Control GAPDH (GAPDH-cDF and GAPDH-cDR) was used as normalizer, listed in Table 1. Real-time PCR was detected under the same conditions with an initial denaturation at 95 C for 15 s, reaction mixtures underwent 40 cycles at 95 C for 5 s and followed by 60 C for 30 s. Samples were also analyzed in triplicates in each trial.


It has been shown that viral load is one of the risk factors in invasive cervical cancer development [19]. Therefore, we detected viral load in different viral physical status. In our study, purely HPV 16 episome contained 238.31 copies per cell in invasive cervical cancer tissues, but purely integrated HPV 16 contained only 52.56 copies per cell. Mean viral load in cases with purely episomal viral genomes was 4.53-fold compared with purely integrated viral genomes. We further analyzed viral load and E6 mRNA transcript levels of HPV16 in different viral physical status, and found that mean E6 expression in cases harboring purely episomal viral genomes was 7.13-fold higher than those harboring purely integrated forms. Furthermore, our result showed that E6 mRNA expression increased simultaneously with the viral loads in HPV 16 episomal genomes, but not in HPV 16 integrated genomes. Similarly, Marongiu L and his collogues previously found that samples harboring solely episomal HPV16 DNA had a higher viral load than samples with solely integrated forms [20]. Thus, our and previously findings suggest that the overexpression of HPV oncogene may be mediated through a high viral load under HPV episomal status without E2 disruption [19]. In fact, intact E2 protein can enhance viral DNA replication by interacting with the viral replication factor E1 and recruiting it to the origin of replication [21, 22], and consequently facilitates viral genome segregation by tethering the viral genomes to host mitotic chromosomes [23].


Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated.


HPV+ cancers comprise over 5% of malignancies worldwide, and rising incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has made this the most common HPV-related cancer in the United States (1). HPV+ OPSCCs are typically sensitive to the combination of radiation plus cisplatin, which is often curative for this disease (2). Impaired DNA repair mechanisms help make HPV+ OPSCCs sensitive as a group to these therapies (3), which kill tumors by increasing reactive oxygen species (ROS) generation beyond cellular antioxidant capacity, leading to uncontrolled damage to DNA, protein, and lipids (4). High cure rates for HPV+ OPSCCs treated with standard therapy have sustained interest in de-escalating cisplatin and radiation therapy, whose toxic sequelae leave lifelong disabilities in survivors (5). However, attempting to supplant cisplatin with anti-EGFR therapy was unsuccessful (6, 7), and radiation de-escalation efforts remain a work in progress. The ability to personalize therapy based on more accurate predictive biomarkers would greatly enhance treatment de-escalation efforts for this disease; however, such innovation remains hindered by limited understanding of the mechanisms underlying divergent responses among HPV+ OPSCCs to cisplatin and radiation.


Our findings add to understanding of how variable HPV oncogene expression affects oropharyngeal cancer clinical behavior. HPV E2 disruption by viral genome integration in a subset of cancers is traditionally thought to derepress E6/E7 expression, and there is some evidence suggesting that loss of E2 expression portends worse prognosis (37). Increased E1^E4 mRNA (38) and decreased E2F target gene dysregulation downstream of E7 (22) have also been linked to worse survival in small clinical cohorts, albeit without mechanistic basis. In addition, E2/E4/E5 expression was observed to predominate over E6/E7 in some OPSCCs (39), although this alternative viral gene expression pattern was not prognostic. Increased E6 splicing is observed in cancer relative to normal viral replication (40) and may indicate that the fl-E6 levels best serving malignant progression are lower than those that serve the viral life cycle. Similarly, chronic in vitro cisplatin exposure is reported to reduce fl-E6 expression (41) and may represent adaptation to mitigate oxidative stress. Taken together with our findings, these prior observations suggest that certain HPV+ cancers achieve competitive advantage through partially preserving p53 function by downregulating fl-E6.


To date, the multimarker transcriptional profiles with prognostic signals for HPV+ OPSCC (21, 60) have not had a clear biologic basis or been generalizable enough for clinical application. Whereas E6 is unlikely to achieve utility as a single biomarker, mitochondrial mass is related to other features of HPV+ OPSCCs that hold promise as prognostic and predictive biomarkers. Image-based quantification of hypoxia as a source of radioresistance is in clinical trials to guide therapy de-escalation for HPV+ OPSCC (61). Because hypoxia induces oxidative stress, tumors with the antioxidant capacity to survive hypoxia may exploit the same antioxidant mechanisms to resist treatment. The benefit of increased mitochondrial function in this context is consistent with decreases in E6/E7 expression and p53 degradation (62) observed under hypoxia in HPV+ cervical cancer cell lines. There is also evidence that genetic silencing of negative regulators of NRF2, a driver of antioxidant gene transcription with downstream and upstream relationships to PGC-1α, confers poor prognosis in HPV+ cancers (12). Therefore, fl-E6 levels may merit joint consideration with NRF2 regulation, hypoxia, and other features linked to antioxidant capacity in developing multimarker predictors of therapy response.


This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.


Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( ), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


Copyright: 2012 Du 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.


Funding: Financial support was provided by the Swedish Institute for Infectious Disease Control, the Swedish Cancer Foundation (100258), the Swedish Research Council (K2011-56X-15282-07-6), the Stockholm Cancer Society (101081), the Stockholm City Council (2010067) and the Karolinska Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 041b061a72


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The Richland County Democratic Executive Committee consists ...

Members

  • Logan Ideas
    Logan Ideas
  • Rezo Titov
    Rezo Titov
  • Jose Roberts
    Jose Roberts
  • Peresvet Nesterov
    Peresvet Nesterov
  • Ishmael Mills
    Ishmael Mills
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