microRNAs are biomarkers of oncogenic human papillomavirus infections

Wang, Xiaohong; Wang, Hsu Kun; Li, Yang; Hafner, Markus; Banerjee, N. Sanjib; Tang, Shuang; Briskin, Daniel; Meyers, Craig; Chow, Louise T.; Xie, Xing; Tuschl, Thomas; Zheng, Zhi-Ming

doi:10.1073/pnas.1401430111

Cited by 174 publications

(189 citation statements)

References 61 publications

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“…The mechanism of PD L1 upregulation by the viral infection will require further study. Possible mechanism would include direct HPV RNA inducement of PD L1, HPV dysregulation of microRNA expression patterns 24 that can, in turn, affect PD L1 production, and more general signals of viral infection such as, for example, production of interferon gamma. Regardless of the mechanism, the possible significance of these findings, which need to be addressed include using PD L1 as a biomarker of productive HPV infection and directing treatment against PD L1 to eradicate HPV infection and the associated lesion, especially in women with squamous cell cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21 = 95%) and cervical squamous cell cancer (56/70 = 80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each Po0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115 = 19%) and ovarian adenocarcinomas (5/40 = 13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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“…Overexpression of miR-92a significantly enhanced cervical cancer cell proliferation by promoting cell cycle transition from G1 to S phase and promoted cell invasion. A study by Wang et al (25) suggested that upregulation of miR-92a may be used as an important biomarker for oncogenic human papillomavirus infections. In the present study, a significant upregulation of miR-92a expression in cervical cancer tissues compared to matched adjacent non-tumor tissues was also observed.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-92a promotes cell viability and invasion in cervical cancer via directly targeting Dickkopf-related protein 3

Luo¹,

Li²,

Yu³

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. was recently reported to have an oncogenic role in cervical cancer; however, the underlying mechanism remains largely unclear. The present study aimed to investigate the expression, clinical significance and regulatory mechanism of miR-92a in cervical cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data indicated that miR-92a was significantly upregulated in cervical cancer tissues compared with matched adjacent non-tumor tissues (P<0.01). High expression of miR-92a was significantly associated with poor differentiation (P=0.031), advanced clinical stage (P=0.011) and lymph node metastasis (P=0.014), but not associated with age, tumor size and distant metastasis. Knockdown of miR-92a significantly inhibited the viability and invasion of cervical cancer HeLa cells, while overexpression of miR-92a significantly enhanced HeLa cell viability and invasion (P<0.01). Luciferase reporter assay identified Dickkopf-related protein 3 (DKK3) as a target gene of miR-92a, and the protein expression of DKK3 was negatively regulated by miR-92a in HeLa cells. Furthermore, overexpression of DKK3 significantly eliminated the stimulative effects of miR-92a on HeLa cell viability and invasion (P<0.01). Additionally, DKK3 was significantly downregulated in cervical cancer tissues compared with adjacent non-tumor tissues (P<0.01), inversely correlated to the miR-92a levels in cervical cancer tissues (P<0.01). In summary, the present study indicated that miR-92a promotes cell viability and invasion in cervical cancer, partly at least, via inhibiting the protein expression of DKK3. Therefore, the present study highlights the clinical significance of the miR-92a/DKK3 axis in cervical cancer.

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“…Primary human foreskin keratinocytes with the HPV18 episomal form (HFK18) were cultured as described previously in EpiLife calcium-free medium (Life Technologies, Thermo Scientific) supplemented with 5% fetal bovine serum (HyClone, GE Healthcare) and human keratinocyte growth supplement (Life Technologies, Thermo Scientific) in the presence of mitomycin C-treated J2 feeder cells (28)(29)(30), and 2.5 mM CaCl 2 was added to induce keratinocyte differentiation.…”

Section: Cell Lines Hek293 Cells (Human Embryonic Kidney Tissue-derimentioning

confidence: 99%

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCEExpression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.H igh-risk human papillomavirus (HPV) is associated with more than 95% of cervical cancer, 40 to 90% of anogenital cancer, and 10 to 60% of oropharyngeal cancer with geographic variation (1). Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regu...

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microRNAs are biomarkers of oncogenic human papillomavirus infections

Cited by 174 publications

References 61 publications

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

MicroRNA-92a promotes cell viability and invasion in cervical cancer via directly targeting Dickkopf-related protein 3

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

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