Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer

Wang, N; Zhan, Ting; Ke, Tie; Huang, Xingyue; Dong, Ke; Wang, Q; Li, H

doi:10.1038/bjc.2013.817

Cited by 91 publications

(87 citation statements)

References 39 publications

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“…Previous studies demonstrated that RRM2 protein levels are increased in cervical cancer cells containing integrated viral genomes (Wang et al, 2014). To determine if RRM2 levels are also increased in lines harboring episomal copies of HPV, we compared the level of RRM2 protein in uninfected human foreskin keratinocytes (HFKs) to HPV31 positive CIN162 cells, which are derived from a CIN1 cervical lesion.…”

Section: Resultsmentioning

confidence: 99%

“…RNR activity is important to genomic integrity, as well as cell viability, with an increase or imbalance of dNTP pools leading to mutagenesis (Hu and Chang, 2007), and decreased dNTP levels leading to impaired DNA replication and repair (Nordlund and Reichard, 2006). Previous studies demonstrated that RRM2 transcript and protein levels are increased in cervical cancer lines containing chromosomally integrated HPV16 and HPV18 genomes (Wang et al, 2014). HPV16 E7 was found to be sufficient to increase RRM2 transcript levels, however, whether RRM2 is increased in lines containing episomal HPV genomes and is important for viral replication has not been examined.…”

Section: Introductionmentioning

confidence: 99%

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HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

et al. 2016

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Productive replication of human papillomaviruses (HPV) is restricted to the uppermost layers of the differentiating epithelia. How HPV ensures an adequate supply of cellular substrates for viral DNA synthesis in a differentiating environment is unclear. Here, we demonstrate that HPV31 positive cells exhibit increased dNTP pools and levels of RRM2, a component of the ribonucleotide reductase (RNR) complex, which is required for de novo synthesis of dNTPs. RRM2 depletion blocks productive replication, suggesting RRM2 provides dNTPs for viral DNA synthesis in differentiating cells. We demonstrate that HPV31 regulates RRM2 levels through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response, which is essential to combat replication stress upon entry into S-phase, as well as for productive replication. Our findings suggest a novel way in which viral DNA synthesis is regulated through activation of ATR and Chk1 and highlight an intriguing new virus/host interaction utilized for viral replication.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

et al. 2016

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“…Although only three patients were assigned to the PR molecular subtype, the hazard for TTT was 9-fold the average, identifying a subset of patients with imminent progression, as also reported by Hose et al 32 The top gene in the GEP4 model, RRM2, is the beta subunit of ribonucleotide reductase (RNR). RRM2 overexpression is associated with cellular invasiveness, metastasis and tumor angiogenesis 33 via activation of the ERK1/2 signaling pathway 34 in cancer. RRM2 expression independently identified 15.2% patients with a 2-year TTT estimate of 75% (Online Supplementary Figure S1).…”

Section: Discussionmentioning

confidence: 99%

Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nGenomics of high-risk SMM haematologica | 2015; 100(9) 1215 Methods Eligibility criteria and study designPatients with SMM seen at the Myeloma Institute for Research and Therapy were included in a prospective, observational clinical trial (SWOG S0120) as part of a national cooperative group trial to identify biological correlates that may relate to progression to symptomatic disease. Other eligibility criteria included no prior therapy for the plasma cell disorder and willingness to submit samples for research. Diagnostic criteria for SMM were based on the International Myeloma Working Group convention.3 All patients signed informed consent, in keeping with the Declaration of Helsinki and federal and institutional guidelines. The protocol was approved by the National Cancer Institute and all participating centers' internal review boards.All patients underwent detailed clinical staging at initial registration, including full blood count, analysis of blood chemistry, and standard MM-related serological and urinary measurements. Nephelometric analysis was performed to determine serum immunoglobulin levels. Immunofixation analyses of serum and urine were performed to define the nature of the monoclonal protein present in serum and/or urine. Bone marrow aspirates and biopsies were obtained for cytological and histopathological evaluation of the degree of plasma cell infiltration, including immunohistochemical clonality assessment. Metaphase karyotyping was performed on at least 20 Giemsa-stained metaphases. 23 In most patients, serum FLC assays were used to quantify k and l light chains. Imaging studies involved standard metastatic bone surveys by X-ray examination, and, when possible, MRI of the entire spine was used to identify focal lesions. The minimum follow-up of patients involved MM-related laboratory studies at 3, 6, and 12 months in the first year, and then every 6 to 12 months. Gene expression profiling and statistical methodsA sample of bone marrow aspirate was collected to isolate CD138 + plasma cells with immunomagnetic bead selection (autoMACS; Miltenyi Biotec) as described elsewhere. 24 The purity of the plasma cells was monitored by flow cytometry and >85% purity was used as a criterion for inclusion of GEP data. Total RNA from these plasma cells was used for the GEP with Affymetrix U133 Plus 2.0 microarrays. We identified patients with SMM and baseline GEP data who were cared for at this institution. We evaluated 54,675 Affymetrix gene probes for their potential to predict time to myeloma therapy (TTT). Probes were ranked by their qvalues; 25 we used 10-fold cross validation to identify the number of genes at the top of this list, which collectively maximized the concordance between risk score and survival. Gene scores were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes. A running log-rank test was used to iden...

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“…The quantitative RT-PCR (qRT-PCR) data were analyzed using the method of 2 j$$Ct relative expression quantity as previously described. 21 All the qRT-PCR reactions were run in triplicate.…”

Section: Rna Isolation and Quantitative Real-time Pcrmentioning

confidence: 99%

MiR-195 Suppresses Cervical Cancer Migration and Invasion Through Targeting Smad3

Zhou¹,

Han²,

Zhou³

et al. 2016

Int J Gynecol Cancer

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Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer

Cited by 91 publications

References 39 publications

HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

MiR-195 Suppresses Cervical Cancer Migration and Invasion Through Targeting Smad3

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