Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue

Cortés-Malagón, Enoc Mariano; Bonilla-Delgado, José; Díaz-Chávez, José; Hidalgo-Miranda, Alfredo; Romero-Córdoba, Sandra; Üren, Aykut; Çelik, Haydar; McCormick, Matthew; Munguía-Moreno, José A.; Ibarra-Sierra, Eloisa; Escobar-Herrera, Jaime; Lambert, Paul F.; Mendoza-Villanueva, Daniel; Bermúdez‐Cruz, Rosa María; Gariglio, Patricio

doi:10.1016/j.virol.2013.08.036

Cited by 31 publications

(39 citation statements)

References 74 publications

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“…Nonetheless, several gene expression profiling studies have been conducted on HPV E7-expressing cells using microarray analysis. The cells employed included mouse cells, cervical cancer cell lines (C33A and CaSki), and PHKs (3,(5)(6)(7)90). However, there are major limitations with the DNA microarray approach, such as the relatively high background noise resulting from solution-based DNA probe hybridization as well as the limited scope of profiling analysis, which is confined by the DNA probe set.…”

Section: Discussionmentioning

confidence: 99%

“…E7 from the high-risk HPV types can abrogate cell cycle checkpoints and induces genomic instability. Although several transcription profiling studies for E7 have been conducted using DNA microarray analysis (3,(5)(6)(7), the HPV E7 activities downstream from, or independent of, pRb responsible for deregulation of cell cycle and induction of genomic instability are not fully understood.…”

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confidence: 99%

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Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Yang

Zhang

Gao

et al. 2016

J Virol

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The E7 oncoprotein of the high-risk human papillomavirus (HPV) plays a major role in HPV-induced carcinogenesis. E7 abrogates the G 1 cell cycle checkpoint and induces genomic instability, but the mechanism is not fully understood. In this study, we performed RNA sequencing (RNA-seq) to characterize the transcriptional profile of keratinocytes expressing HPV 16 (HPV-16) E7. At the transcriptome level, 236 genes were differentially expressed between E7 and vector control cells. A subset of the differentially expressed genes, most of them novel to E7-expressing cells, was further confirmed by real-time PCR. Of interest, the activities of multiple transcription factors were altered in E7-expressing cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were investigated. The upregulated genes were enriched in cell cycle and DNA replication, as well as in the DNA metabolic process, transcription, DNA damage, DNA repair, and nucleotide metabolism. Specifically, we focused our studies on the gene encoding WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein), one of the genes that was upregulated in E7-expressing cells. WDHD1 is a component of the replisome that regulates DNA replication. Recent studies suggest that WDHD1 may also function as a DNA replication initiation factor as well as a G 1 checkpoint regulator. We found that in E7-expressing cells, the steady-state level of WDHD1 protein was increased along with the half-life. Moreover, downregulation of WDHD1 reduced E7-induced G 1 checkpoint abrogation and rereplication, demonstrating a novel function for WDHD1. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. IMPORTANCEThe high-risk HPV types induce cervical cancer and encode an E7 oncoprotein that plays a major role in HPV-induced carcinogenesis. However, the mechanism by which E7 induces carcinogenesis is not fully understood; specific anti-HPV agents are not available. In this study, we performed RNA-seq to characterize transcriptional profiling of keratinocytes expressing HPV-16 E7 and identified more than 200 genes that were differentially expressed between E7 and vector control cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were identified. Significantly, the WDHD1 gene, one of the genes that is upregulated in E7-expressing cells, was found to play an important role in E7-induced G 1 checkpoint abrogation and rereplication. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. H uman papillomaviruses (HPVs) are small DNA viruses that replicate in squamous epithelia. Specific types of HPV (highrisk HPVs) are the causative agents for cervical and several other cancers (1). The transforming properties of high-risk HPVs such as HPV 16 (HPV-16) primarily depend on E7 as well as E6 oncogenes (1, 2). HPV E6 and E7 proteins promote the degradation of p53 and pRb, respectively (3, 4). E7 from the high-risk...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Yang

Zhang

Gao

et al. 2016

J Virol

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“…Recently, there has been increasing evidence that demonstrates the cooperation of estrogen and HPV infection in the malignant transformation of cervical epithelium [13][14][15].…”

Section: Resultsmentioning

confidence: 99%

“…T47D breast cancer cells were employed as a positive control for HSD17B1 transcript and protein identification. capable of supporting cervical carcinogenesis [13][14][15][25][26][27][28][29][30][31]]. An eight-fold increase in HPV16 transcripts was observed during treatment of SiHa cells with E2 [25].…”

Section: Resultsmentioning

confidence: 99%

“…Other risk factors for CC development include a complex interaction between genetic and epigenetic changes and the use of hormonal contraceptives, early sexual initiation, multiparity, smoking, infection with Chlamydia trachomatis, and others [8][9][10][11][12]. Moreover, several findings have demonstrated the role of 17b-estradiol [E2] in cervical carcinogenesis [13][14][15]. The E2 production mainly takes place in the ovaries, although this steroid hormone can also be biosynthesized by other pathways in peripheral tissues [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Increased 17ß-hydroxysteroid dehydrogenase type 1 levels in primary cervical cancer

Tomaszewska

Roszak

Pawlik

et al. 2015

Biomedicine & Pharmacotherapy

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Signaling pathways in HPV‐associated cancers and therapeutic implications

Chen

2015

Reviews in Medical Virology

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Human papillomaviruses (HPVs) are small double-stranded circular DNA viruses with 8 kb genomes. So far, more than 150 HPVs have been identified, and 12 types of HPVs have been conclusively linked to cancer by the International Agency for Research on Cancer/World Health Organization. Expression of HPV E5, E6 and E7 oncoproteins can alter multiple signaling pathways to cause cancer. In this review, the signaling pathways activated by these oncoproteins are summarized, and targeted therapy against key signaling molecules is described. E6 can inactivate tumor protein 53 and PDZ (post synaptic density protein-drosophila disk large tumor suppressor-zonula occludens-1 proteins) while stimulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), Wnt and Notch pathways. E7 can inhibit retinoblastoma protein and stimulate the PI3K/Akt pathway. Both E6 and E7 can deregulate cellular microRNA expression, which can alter cellular signaling pathways. E5 can sensitize epidermal growth factor receptor to epidermal growth factor to increase activation of PI3K/Akt and mitogen-activated protein kinase pathways. E5 can also inhibit the extrinsic apoptotic pathway. These altered signaling pathways could be critical for the initiation and maintenance of HPVassociated cancers. Therefore, targeted therapy against the key signaling molecules has therapeutic implications. Among these, the possibilities of targeting PI3K/Akt, mammalian target of rapamycin, epidermal growth factor receptor and vascular endothelial growth factor have been extensively studied in many cancers. Some inhibitors have been studied in cervical cancer in both animal models and clinical trials. Although the results are promising, further investigation is warranted.

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Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue

Cited by 31 publications

References 74 publications

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Increased 17ß-hydroxysteroid dehydrogenase type 1 levels in primary cervical cancer

Signaling pathways in HPV‐associated cancers and therapeutic implications

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