scholarly journals The Effect of Productive HPV16 Infection on Global Gene Expression of Cervical Epithelium

2018 ◽  
Author(s):  
Sa Do Kang ◽  
Sreejata Chatterjee ◽  
Samina Alam ◽  
Anna C. Salzberg ◽  
Janice Milici ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Early Stage ◽  
Therapeutic Targets ◽  
Global Gene Expression ◽  
Hpv Infection ◽  
Cervical Tissue ◽  
First Time ◽  
Hpv16 Infection

AbstractHuman papillomavirus (HPV) infection is the world’s most common sexually transmitted infection, and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early pre-neoplastic stages of infection. We show for the first time, global gene expression changes of early stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures that produce high levels of progeny virions.cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels including UBC, which was central to the protein association network of immune response genes, and top downregulated genes RPTN, SERPINB4, KRT23, and KLK8. In particular, KLK8 and SERPINB4 have shown to be upregulated in cancer, which contrasts our results.Organotypic raft cultures that allow full progression of the HPV life-cycle have allowed us to identify novel gene modulations and potential therapeutic targets of early stage HPV infection in cervical tissue. Additionally, our results suggest that early stage productive infection and cancerous stages of infection are distinct disease states expressing different transcriptomes.ImportancePersistent HPV infection is responsible for most cases of cervical cancer. Transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages, and may lead to development of new therapeutic targets.

scholarly journals Effect of Productive Human Papillomavirus 16 Infection on Global Gene Expression in Cervical Epithelium

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Sa Do Kang ◽  
Sreejata Chatterjee ◽  
Samina Alam ◽  
Anna C. Salzberg ◽  
Janice Milici ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Human Papillomavirus ◽  
Early Stage ◽  
Global Gene Expression ◽  
Hpv Infection ◽  
Cervical Tissue ◽  
First Time ◽  
Hpv16 Infection

ABSTRACTHuman papillomavirus (HPV) infection is the world's most common sexually transmitted infection and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early preneoplastic stages of infection. We show for the first time the global gene expression changes during early-stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures, which produce high levels of progeny virions. cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels, includingUBC, which was central to the protein association network of immune response genes, and top downregulated genesRPTN,SERPINB4,KRT23, andKLK8. In particular,KLK8andSERPINB4were shown to be upregulated in cancer, which contrasts with the gene regulation during the productive replication stage. Organotypic raft cultures, which allow full progression of the HPV life cycle, allowed us to identify novel gene modulations and potential therapeutic targets of early-stage HPV infection in cervical tissue. Additionally, our results suggest that early-stage productive infection and cancerous stages of infection are distinct disease states expressing different host transcriptomes.IMPORTANCEPersistent HPV infection is responsible for most cases of cervical cancer. The transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at the precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages and may lead to the development of new therapeutic targets.

Correlation Between IL-10 Gene Expression and HPV Infection in Cervical Cancer: A Mechanism for Immune Response Escape

2008 ◽  
Vol 26 (10) ◽  
pp. 1037-1043 ◽  
Author(s):  
Victor H. Bermúdez-Morales ◽  
Lourdes X. Gutiérrez ◽  
Juan M. Alcocer-González ◽  
Ana Burguete ◽  
Vicente Madrid-Marina
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Hpv Infection

scholarly journals Low proteolytic processing of histone H3 in cervical tissue positive to hrHPV

2021 ◽  
Author(s):  
Sofia L. Alcaraz-Estrada ◽  
Nicolás Serafín-Higuera ◽  
Roberto Ramos-Mondragón ◽  
Octavio D. Reyes-Hernández ◽  
Gabriela Figueroa-González ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Histone H3 ◽  
Hpv Infection ◽  
Proteolytic Processing ◽  
Epigenetic Mechanism ◽  
Cervical Carcinogenesis ◽  
Epigenetic Alterations ◽  
Cervical Tissue ◽  
Primary Risk Factor

Abstract During the different stages of cervical carcinogenesis there is an accumulation of epigenetic alterations leading to changes in gene expression. High-risk human papillomavirus (hrHPV) is a primary risk factor for cervical cancer (CC). Impaired proteolytic processing of histone H3 constitutes a potential epigenetic mechanism in CC. However, whether this event occurs in early stages of the HPV infection is unknown. Using human cervical samples with normal pathology but positive and negative to hrHPV, we identified that the H3 cleavage was low in the hrHPV positive cervix compared to the hrHPV negative cervix. These results suggest that low H3 processing previously observed in CC may be a primary effect of hrHPV infection.

scholarly journals Integrative machine learning analysis of multiple gene expression profiles in cervical cancer

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5285 ◽  
Author(s):  
Mei Sze Tan ◽  
Siow-Wee Chang ◽  
Phaik Leng Cheah ◽  
Hwa Jen Yap
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Cervical Cancer ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Hpv Infection ◽  
Gene Set Enrichment Analysis ◽  
Multiple Gene ◽  
Cervical Cancers ◽  
Learning Analysis

Although most of the cervical cancer cases are reported to be closely related to the Human Papillomavirus (HPV) infection, there is a need to study genes that stand up differentially in the final actualization of cervical cancers following HPV infection. In this study, we proposed an integrative machine learning approach to analyse multiple gene expression profiles in cervical cancer in order to identify a set of genetic markers that are associated with and may eventually aid in the diagnosis or prognosis of cervical cancers. The proposed integrative analysis is composed of three steps: namely, (i) gene expression analysis of individual dataset; (ii) meta-analysis of multiple datasets; and (iii) feature selection and machine learning analysis. As a result, 21 gene expressions were identified through the integrative machine learning analysis which including seven supervised and one unsupervised methods. A functional analysis with GSEA (Gene Set Enrichment Analysis) was performed on the selected 21-gene expression set and showed significant enrichment in a nine-potential gene expression signature, namely PEG3, SPON1, BTD and RPLP2 (upregulated genes) and PRDX3, COPB2, LSM3, SLC5A3 and AS1B (downregulated genes).

scholarly journals INFLUENZA INFLAMMATION BIOMARKERS FEATURES

2019 ◽  
Vol 1 (3) ◽  
pp. 67-73
Author(s):  
T. P. Ospelnikova ◽  
O. V. Morozova ◽  
S. A. Andreeva ◽  
E. I. Isaeva ◽  
L. V. Kolodyazhnaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Influenza Virus ◽  
Magnetic Beads ◽  
Early Stage ◽  
Influenza Infection ◽  
Rt Pcr ◽  
The Matrix ◽  
Polarization Coefficient ◽  
Th1 Immune Response

Aim. Analysis of inflammation biomarkers using reverse transcription with real time PCR (RT-PCR-RT) and multiplex immunofluorescent analysis xMAP with magnetic beads for the influenza infection. Materials and methods. Analysis of nasopharyngeal swabs, lymphocytes and blood sera of 10 patients with influenza and 10 donors was performed during the first 2 days of the disease by means of RT-PCR-RT and xMAP using the kit «37-plex» (BioRad). Results.The influenza virus A was revealed in 4 samples, the influenza virus B — in 6 swabs without mixed infections with other respiratory viruses. Analysis of the interferons (IFN) showed IFNα gene expression activation in patients’ lymphocytes but both the detection rate and the concentrations of IFNβ, IFNγ and IFNλ RNA were similar for patients and healthy donors. Among 37 inflammation biomarkers the concentrations of 7 proteins were enhanced including IFNα2, cytokines of TNF family (APRIL and BAFF), their soluble receptors sTNF-R1 and sTNF-R2, protein osteopontin and IL10. The concentrations of the complex of glycoprotein gp130 with the soluble receptor IL6 gp130/sIL-6Rβ and the matrix metalloprotease ММР-1 were reduced in patients’ sera. The polarization coefficient PI=[IL10]/[IFNγ]=0.53 for influenza samples suggested Th1 immune response. Conclusion. At the early stage of the influenza infection IFNα gene expression activation along with the induction of TNF family cytokines (APRIL and BAFF), their receptors (sTNF-R1 and sTNF-R2) and osteopontin as well as the inhibition of the complex gp130/sIL-6Rβ and metalloprotease ММР-1 were shown. Th1 immune response regulated by IL10 resulted in the recovery of the patients without complications.

Understanding the development of cervical cancer - Joint efforts to improve HPV and cervical cancer diagnosis

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 58-59
Author(s):  
Kirvis Janneth Torres Poveda ◽  
Vicente Madrid-Marina
Keyword(s):  
Cervical Cancer ◽  
Immune System ◽  
Cancer Diagnosis ◽  
Causes Of Death ◽  
Hpv Infection ◽  
Cervical Tissue ◽  
Papilloma Virus ◽  
Microbial Strains ◽  
Malignant Lesions ◽  
Natural Microbiota

Cervical cancer is one of the leading causes of death among women, with 99% of the cases linked to human papilloma virus (HPV) infection. The immune system, in conjunction with the natural microbiota that proliferates in cervical tissue, has a crucial role in eradicating the virus, and preventing the progression of malignant lesions. A failure in these controlling mechanisms may be at the root of cervical cancer (CC). Dr Kirvis Torres-Poveda and Dr Vicente Madrid-Marina are investigating the mechanisms in which these imbalances occur and pinpointing specific microbial strains that lead to the development of cervical cancer after HPV infection to determine the correlation between vaginal microbiomes, HPV, and cervical cancer

Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling

2011 ◽  
Vol 300 (1) ◽  
pp. F177-F188 ◽  
Author(s):  
Masanori Kugita ◽  
Kazuhiro Nishii ◽  
Miwa Morita ◽  
Daisuke Yoshihara ◽  
Hiroe Kowa-Sugiyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Kidney Disease ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Early Stage ◽  
Global Gene Expression ◽  
Rt Pcr ◽  
Polycystic Kidney ◽  
Global Gene Expression Profiling

Han:SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated “Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation,” “LPS/IL-1-Mediated Inhibition of RXR Function,” and “Liver X Receptor (LXR)/RXR Activation.” These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.

Association of phosphatidylinositol 3-kinase (PI3K) pathway activation with increased immune checkpoint expression in colorectal cancer (CRC) patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
Maliha Nusrat ◽  
Jason Roszik ◽  
Riham Katkhuda ◽  
David Menter ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Protein Expression ◽  
Immune Cell ◽  
Early Stage ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Pik3ca Mutations ◽  
The Impact

653 Background: PI3K pathway is a known modulator of anti-tumor immune response and is frequently activated in CRC through genetic alterations such as PTEN loss (PTENloss) and PIK3CA mutations (PIK3CAmut). This study aims to determine the impact of these alterations on immune cell infiltration, priming and activation in early stage CRC patients (pts). Methods: Immune infiltrates and checkpoints were evaluated using quantitative immunohistochemistry (IHC) on primary CRC (N = 59) for both center of tumor (CT) and invasive margin (IM). Pts were evaluated by presence or absence of either PTENloss or PIK3CAmut (collectively termed PI3K pathway alterations). Microsatellite unstable (MSI) and stable (MSS) tumors were analyzed separately. Clinicopathologic data was examined for potential associations with PI3K pathway alterations. Separately, mRNA data (Agilent) was obtained for immune related genes from an internal cohort with PTEN and PIK3CA annotation (N = 73). Results: 59 pts comprised IHC cohort (40 MSS, 19 MSI); 23 pts (39%) had PTENloss or PIK3CAmut. In Agilent cohort, 16 of 73 pts (22%) had PI3K pathway alterations. In MSS CRC, these alterations were more common in CMS1 (p = 0.03), on right side (p = 0.048) and with peritumoral lymphocytes (p = 0.031). MSS pts with PI3K pathway alterations had higher PD1 protein expression (p = 0.04), 2.1 and 2.3 times increased density of CD3+ (p = 0.01) and CD8+ (p = 0.04) cells respectively, and higher Granzyme B protein expression (p = 0.04) in the CT. These pts also had higher PDL1 gene expression (p = 0.046). MSS CRC pts with PIK3CAmut similarly had 2 times more PDL1 protein expression in epithelial cells of the IM (p = 0.01). Alternate checkpoints were also increased in pts with PI3K pathway alterations, including higher protein expression of LAG3 in CT (P = 0.046) and higher gene expression of CTLA4, TIM3, and TIGIT (P < 0.05 for all). Conclusions: PI3K pathway activated MSS CRC is associated with increased immune engagement, but also upregulation of key immune checkpoints in early stage tumors resulting in an ineffective immune response. Combination of PI3K pathway inhibition with immunotherapy merits investigation in this subset of pts.

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