scholarly journals E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

2020 ◽  
Author(s):  
Ethan L. Morgan ◽  
James A. Scarth ◽  
Molly R. Patterson ◽  
Christopher W. Wasson ◽  
Georgia C. Hemingway ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Human Papillomaviruses ◽  
Signalling Pathway ◽  
Viral Oncoprotein ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
Novel Therapeutic

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

scholarly journals Disruption of repressive p130–DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells

2011 ◽  
Vol 92 (11) ◽  
pp. 2620-2627 ◽  
Author(s):  
Nurshamimi Nor Rashid ◽  
Rohana Yusof ◽  
Roger J. Watson
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Human Papillomaviruses ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Hpv16 E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so-called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130–DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130–DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130–DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130–DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130–DREAM complex.

Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin

2012 ◽  
Vol 319 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Elad Milrot ◽  
Anna Jackman ◽  
Tatiana Kniazhanski ◽  
Pinhas Gonen ◽  
Eliezer Flescher ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Methyl Jasmonate ◽  
Cancer Cells ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

scholarly journals Leukemia Inhibitory Factor Downregulates Human Papillomavirus-16 Oncogene Expression and Inhibits the Proliferation of Cervical Carcinoma Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Joseph M. Bay ◽  
Bruce K. Patterson ◽  
Nelson N. H. Teng
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Cells ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Human Papillomavirus 16 ◽  
Oncogene Expression ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

The constitutive proliferation and resistance to differentiation and apoptosis of neoplastic cervical cells depend on sustained expression of human papillomavirus oncogenes. Inhibition of these oncogenes is a goal for the prevention of progression of HPV-induced neoplasias to cervical cancer. SiHa cervical cancer cells were transfected with an HPV-16 promoter reporter construct and treated with leukemia inhibitory factor (LIF), a human cytokine of the interleukin 6 superfamily. SiHa and CaSki cervical cancer cells were also assessed for proliferation by MTT precipitation, programmed cell death by flow cytometry, and HPV E6 and E7 expression by real-time PCR. LIF-treated cervical cancer cells showed significantly reduced HPV LCR activation, reduced levels of E6 and E7 mRNA, and reduced proliferation. We report the novel use of LIF to inhibit viral oncogene expression in cervical cancer cells, with concomitant reduction in proliferation suggesting re-engagement of cell-cycle regulation.

Abstract 679: ABI-231: A novel small molecule suppresses tumor growth and metastatic phenotypes of cervical cancer cells via targeting HPV E6 and E7

2018 ◽  
Author(s):  
Vivek K. Kashyap ◽  
Bilal B. Hafeez ◽  
Qinghai Wang ◽  
Neeraj Chauhan ◽  
Prashanth K. Nagesh ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Small Molecule ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

scholarly journals The endonuclease APE1 processes miR-92b formation, thereby regulating expression of the tumor suppressor LDLR in cervical cancer cells

2019 ◽  
Vol 11 ◽  
pp. 175883591985585 ◽  
Author(s):  
Yi Sun ◽  
Yun Feng ◽  
Guiqian Zhang ◽  
Ya Xu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cervical Carcinoma ◽  
Cell Cycle Progression ◽  
Endonuclease Activity ◽  
Cycle Progression ◽  
Cervical Cancer Cells ◽  
Novel Therapeutic

Background: The molecular mechanisms underlying cervical cancer require elucidation to identify novel therapeutic targets. Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is a multifunctional apurinic/apyrimidinic (AP) endonuclease that influences the transcription of many cancer-related genes via microRNome regulation. Herein, we examine the role of miR-92b-3p (hereinafter miR-92b), whose processing may be regulated by APE1, in cervical cancer progression. Methods: APE1’s processing of miR-92b from its pri-miR form was measured by a quantitative reverse transcription polymerase chain reaction (qRT-PCR)-based ratio. APE1’s endonuclease activity was measured with AP-site incision assays. APE1-DROSHA interaction was studied with immunofluorescence, confocal and proximity ligation analyses. The miR-92b’s targeting of low-density lipoprotein receptor (LDLR) was investigated with luciferase reporter assays. The miR-92b mimics and shRNA-based miR-92b silencing, as well as LDLR overexpression and short interfering RNA (siRNA)-based LDLR silencing, were employed in CaSki and SiHa cervical cancer cells. Cell proliferation and chemosensitivity to paclitaxel and cisplatin were assayed. Cell-cycle progression and apoptosis were assessed by flow cytometry. Tumor growth was studied in a murine xenograft model. Results: APE1’s endonuclease activity, via association with the DROSHA-processing complex, is necessary for processing mature miR-92b, thereby regulating expression of miR-92b’s direct target LDLR. The miR-92b promotes cell proliferation in vitro and in vivo, promotes cell-cycle progression, and reduces apoptosis and chemosensitivity. LDLR silencing recapitulated miR-92b’s transformative effects, while LDLR overexpression rescued these effects. Conclusions: APE1 enhances miR-92b processing, thereby suppressing LDLR expression and enhancing cervical carcinoma progression. Our identification of the novel APE1-miR-92b-LDLR axis improves our understanding of the complex pathogenesis of cervical carcinoma and reveals a novel therapeutic strategy for combating this disease.

scholarly journals Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Hongpeng He ◽  
Xiang Liu ◽  
Yue Liu ◽  
Mengmeng Zhang ◽  
Yongwei Lai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Cells ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Human Papillomaviruses ◽  
Cervical Cancer Cells ◽  
E6 And E7

ABSTRACT TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53 response elements in the TMPOP2 promoter to repress the transcription of the TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (lncRNA) TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest, and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities. IMPORTANCE Human papillomaviruses 16 and 18 (HPV16/18) are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of long noncoding RNAs (lncRNAs) in cervical cancer, although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings of the oncogenic activities of human papillomaviruses and lncRNAs.

Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells

2011 ◽  
Vol 412 (2) ◽  
pp. 328-333 ◽  
Author(s):  
Kiwon Lee ◽  
Ah-Young Lee ◽  
Yunhee Kim Kwon ◽  
Hyockman Kwon
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

Reducing invasion potential of cervical cancer cells via targeted knockdown of c-Jun.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22005-e22005
Author(s):  
Grace Pei Chien Yee ◽  
Paul L. De Souza ◽  
Levon M. Khachigian
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Hela Cells ◽  
Human Papillomaviruses ◽  
Mrna Levels ◽  
Down Regulation ◽  
Recurrent Cervical Cancer ◽  
Invasion Potential ◽  
Cervical Cancer Cells

e22005 Background: Despite recent advent of vaccines for human papillomaviruses (HPV) in cervical cancer and increasing efforts to improve therapy, deaths still average 275,000 annually worldwide, with most women succumbing to recurrent or metastatic disease. The c-Jun oncogene is a subunit of the activating protein-1 (AP-1) transcription factor and is strongly expressed in cervical cancer, regulating the expression of HPV16 and 18 genes. AP-1 plays a major role in cell growth, migration and apoptosis in many cell types. This study examined the role of c-Jun in modulating HeLa proliferation, migration, apoptosis and invasion as well as susceptibility to cisplatin. Methods: Transient knockdown and over-expression of c-Jun was performed in HeLa cervical cancer cells using Dharmacon c-Jun siRNA and Origene Jun expression vector. c-Jun and downstream gene/protein expression was confirmed by western blot and real-time PCR and cells subject to proliferation, in vitro wound and matrigel dual-chamber transwell assays. Flow cytometry was used for analysis of cell cycle and apoptosis. Results: c-Jun protein and mRNA levels were reduced by c-Jun siRNA. c-Jun silencing inhibited cervical cancer cell proliferation. Significantly, c-Jun suppression dramatically reduced HeLa migration and invasion and targeted down-regulation of cyclooxygenase-2 (Cox2), interleukin-6 (IL-6), metalloproteinases (MMP)-1, -9 and -13 as well as HPV18 E6 and E7, genes highly expressed in cervical cancer and associated with metastatic growth. Direct siRNA knockdown of Cox2 in HeLa also reduced MMP1 and MMP9 expression suggesting an intermediary link. In HeLa cells over-expressing c-Jun, cell proliferation was not significantly increased but cell invasiveness was markedly enhanced in parallel with enhanced MMP-1 expression. Modulation of c-Jun expression did not interfere with susceptibility of HeLa cells to apoptosis in the presence of cisplatin. Conclusions: Reduced invasion potential of HeLa cells after c-Jun knockdown suggests a potential target in treatment of metastatic and recurrent cervical cancer. Data suggest a mechanism involving down-regulation of Cox2 and MMP-1 and -9 expression.

scholarly journals Nucleolin as Activator of Human Papillomavirus Type 18 Oncogene Transcription in Cervical Cancer

2002 ◽  
Vol 196 (8) ◽  
pp. 1067-1078 ◽  
Author(s):  
Edgar Grinstein ◽  
Peter Wernet ◽  
Peter J.F. Snijders ◽  
Frank Rösl ◽  
Inge Weinert ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Cancer Cells ◽  
Binding Activity ◽  
Human Papillomaviruses ◽  
Cervix Uteri ◽  
Cell Protein ◽  
Critical Event ◽  
Cervical Cancer Cells ◽  
E6 And E7

High risk human papillomaviruses (HPVs) are central to the development of cervical cancer and the deregulated expression of high risk HPV oncogenes is a critical event in this process. Here, we find that the cell protein nucleolin binds in a sequence-specific manner to the HPV18 enhancer. The DNA binding activity of nucleolin is primarily S phase specific, much like the transcription of the E6 and E7 oncoproteins of HPV18 in cervical cancer cells. Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18+ cervical cancer cell growth. Furthermore, nucleolin controls the chromatin structure of the HPV18 enhancer. In contrast, HPV16 oncogene transcription and proliferation rates of HPV16+ SiHa cervical cancer cells are independent of nucleolin activity. Moreover, nucleolin expression is altered in HPV18+ precancerous and cancerous tissue from the cervix uteri. Whereas nucleolin was homogeneously distributed in the nuclei of normal epithelial cells, it showed a speckled nuclear phenotype in HPV18+ carcinomas. Thus, the host cell protein nucleolin is directly linked to HPV18-induced cervical carcinogenesis.

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