Identification of High-Risk Human Papillomavirus (hrHPV)-Associated Genes in Early Stage Cervical Squamous Cell Carcinomas

Hu, Yanjia; Y, Liu; Cb, Liu; Zq, Ling

doi:10.1177/147323001103900303

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…5,26 Because a gradual absence of IL-1A was also found in cervical tissue sections, inactivation of IL-1A signaling apparently inhibits its central role in the balance between inflammation and antiviral immunity against an HPV infection, thereby significantly contributing to the development of cervical cancer. 27 On the basis of the previously mentioned information, we suggested that IL-1AY511C/T polymorphism could be involved in cervical cancer pathogenesis and may be a potential relevant factor for cervical cancer by affecting IL-1 production or altering levels of IL-1 gene expression.…”

Section: Discussionmentioning

confidence: 84%

Interleukin 1β and Interleukin 1 Receptor Antagonist Gene Polymorphisms and Cervical Cancer: A Meta-analysis

Wu¹,

Hu²,

Chen³

et al. 2014

Int J Gynecol Cancer

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Section: Discussionmentioning

confidence: 84%

Interleukin 1β and Interleukin 1 Receptor Antagonist Gene Polymorphisms and Cervical Cancer: A Meta-analysis

Wu¹,

Hu²,

Chen³

et al. 2014

Int J Gynecol Cancer

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“…Other authors also recommend the use of at least two reference genes for human tissues [43], [44]. However, even though it has been widely accepted that one of the best ways to normalize the qPCR data is to use at least 2 to 3 reference genes, several studies of cervical cancer continue to use the most well-known reference genes such as GAPDH [23], [45], ACTB [30], EEF1A1 [46] and RNU6 [15], [24]–[27], [46]–[51], as a single reference gene and without mentioning whether this stage has been performed accurately. Furthermore, even though it has been established that a normalization standard must reflect the quantity and size of the target of interest to obtain comparable samples [12], [22]; some studies have used an mRNA as a reference gene to normalize the miRNA expression levels in cervical cancer [25], [51].…”

Section: Discussionmentioning

confidence: 99%

Quantifying mRNA and MicroRNA with qPCR in Cervical Carcinogenesis: A Validation of Reference Genes to Ensure Accurate Data

et al. 2014

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A number of recent studies have catalogued global gene expression patterns in a panel of normal, tumoral cervical tissues so that potential biomarkers can be identified. The qPCR has been one of the most widely used technologies for detecting these potential biomarkers. However, few studies have investigated a correct strategy for the normalization of data in qPCR assays for cervical tissues. The aim of this study was to validate reference genes in cervical tissues to ensure accurate quantification of mRNA and miRNA levels in cervical carcinogenesis. For this purpose, some issues for obtaining reliable qPCR data were evaluated such as the following: geNorm analysis with a set of samples which meet all of the cervical tissue conditions (Normal + CIN1 + CIN2 + CIN3 + Cancer); the use of individual Ct values versus pooled Ct values; and the use of a single (or multiple) reference genes to quantify mRNA and miRNA expression levels. Two different data sets were put on the geNorm to assess the expression stability of the candidate reference genes: the first dataset comprised the quantities of the individual Ct values; and the second dataset comprised the quantities of the pooled Ct values. Moreover, in this study, all the candidate reference genes were analyzed as a single “normalizer”. The normalization strategies were assessed by measuring p16INK4a and miR-203 transcripts in qPCR assays. We found that the use of pooled Ct values, can lead to a misinterpretation of the results, which suggests that the maintenance of inter-individual variability is a key factor in ensuring the reliability of the qPCR data. In addition, it should be stressed that a proper validation of the suitability of the reference genes is required for each experimental setting, since the indiscriminate use of a reference gene can also lead to discrepant results.

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“…These cells are important sensors of pathogens and danger signals that mediate immune responses, supporting the notion that keratinocytes, which are the main target of HPV infection, also have to be considered as central nonprofessional immune competent cells of the mucosa [10], [31]. Although IL-1β was recently identified to be targeted by high-risk HPV as a central hub within the network of innate immunity [5] and down-regulated in cervical tumors [32]–[34], our knowledge about its function and regulation in the context of HPV-induced carcinogenesis is still rudimentary.…”

Section: Introductionmentioning

confidence: 99%

Post-Translational Control of IL-1β via the Human Papillomavirus Type 16 E6 Oncoprotein: A Novel Mechanism of Innate Immune Escape Mediated by the E3-Ubiquitin Ligase E6-AP and p53

et al. 2013

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Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1β) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1β production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1β processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1β regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1β was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1β that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1β is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1β levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1β regulation which ultimately inhibits the secretion of IL-1β in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1β towards cervical cancer could be discerned. Hence, attenuation of IL-1β by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy.

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Identification of High-Risk Human Papillomavirus (hrHPV)-Associated Genes in Early Stage Cervical Squamous Cell Carcinomas

Cited by 7 publications

References 56 publications

Interleukin 1β and Interleukin 1 Receptor Antagonist Gene Polymorphisms and Cervical Cancer: A Meta-analysis

Interleukin 1β and Interleukin 1 Receptor Antagonist Gene Polymorphisms and Cervical Cancer: A Meta-analysis

Quantifying mRNA and MicroRNA with qPCR in Cervical Carcinogenesis: A Validation of Reference Genes to Ensure Accurate Data

Post-Translational Control of IL-1β via the Human Papillomavirus Type 16 E6 Oncoprotein: A Novel Mechanism of Innate Immune Escape Mediated by the E3-Ubiquitin Ligase E6-AP and p53

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