Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Harden, Mallory E.; Prasad, Nripesh; Griffiths, Anthony John; Münger, Karl

doi:10.1128/mbio.02170-16

Cited by 61 publications

(78 citation statements)

References 66 publications

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“…Infection with other viruses is known to alter host miRNAs, and some of these changes have been proposed to be advantageous for viral replication (Amaral et al, 2017 (HIV-1); Sun et al, 2016 (HIV-1); Bruce and Alcorn, 2011 (RSV); Lagos et al 2010 (KSHV); Harden et al, 2017a and b (HPV); Marthaler et al, 2017 (HPV); Melar-New and Laimins, 2010 (HPV); Gunasekharan et al, 2013 and 2016 (HPV); Linnstaedt et al, 2010 (EBV); Skalsky and Cullen, 2010 (EBV); Wang et al, 2017 (HCMV); Saldaña et al, 2017 (Zika)). MMTV is transmitted to the virgin mammary gland during puberty by infected B and T lymphocytes (Golovkina et al, 1992 and 1998; Held et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

et al. 2018

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Mouse mammary tumor virus (MMTV) induces breast cancer in mice in the absence of known virally-encoded oncogenes. Tumorigenesis by MMTV is thought to occur primarily through insertional mutagenesis, leading to the activation of cellular proto-oncogenes and outgrowth of selected cells. Here we investigated whether MMTV encodes microRNAs (miRNAs) and/or modulates host miRNAs that could contribute to tumorigenesis. High throughput small RNA sequencing analysis of MMTV-infected cells and MMTV-induced mammary tumors demonstrates that MMTV does not encode miRNAs. However, infected tissues have altered levels of several host miRNAs, including increased expression of members of the oncogenic miRNA cluster, miR-17-92. Notably, similar changes in miRNA levels have been previously reported in human breast cancers. Combined, our results demonstrate that virally encoded miRNAs do not contribute to MMTV-mediated tumorigenesis, but that changes in specific host miRNAs in infected cells may contribute to virus replication and tumor biology.

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Section: Discussionmentioning

confidence: 99%

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

et al. 2018

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“…Primary human foreskin keratinocytes (HFKs) were isolated from a pool of de-identified newborn foreskins and cultured as previously described (Harden et al, 2017). CaSki, C33A, HeLa and SiHa cells (ATCC) were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 50 U/ml penicillin and 50 mg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously investigated modulation of cellular miR levels in response to HPV16 E6/E7 expression in primary human epithelial cells (Harden et al, 2017). Given that the high-risk HPV E6 and E7 proteins are consistently expressed in cervical carcinoma lines, that HPV positive cervical carcinoma lines expressed DROSHA at higher levels than the HPV negative C33A line and the fact that DROSHA expression was shown to only affect expression of a small subset of miRs in cervical cancer lines, we set out to determine whether HPV E6 and/or E7 expression may cause altered DROSHA and/or DICER levels.…”

Section: Introductionmentioning

confidence: 99%

Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins

Harden

Münger

2017

Virology

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Many tumors, including cervical carcinoma, show dysregulated expression of the microRNA processing machinery, specifically DROSHA and DICER. Some cervical cancers exhibit chromosome 5p amplifications and DROSHA is the most significantly upregulated transcript and is observed in all tumors with 5p gain. DROSHA and DICER mRNA levels, however, are higher in HPV positive cancer lines than in an HPV negative cervical carcinoma line. We show that high-risk HPV E6/E7 expression in HPV negative C33A cervical carcinoma cells and primary human epithelial cell causes increased expression of DROSHA and DICER mRNA and protein. Most importantly, many DROSHA regulated microRNAs are dysregulated in HPV16 E6/E7 expressing cells. These results suggest that increased DROSHA levels contribute to HPV16 E6/E7 dysregulation of cellular microRNA expression.

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“…For instance, miR-203 levels are decreased by both E6 and E7 in differentiating HPV-positive epithelial cells (18,20), resulting in the retention of high levels of p63 that are critical for maintaining cells active in the cell cycle and for efficient viral genome amplification (19). HPV proteins also reduce the expression of miR-145, which regulates the levels of the cellular transcription factor KLF-4, that in turn regulates cell cycle progression in differentiating cells (21).…”

mentioning

confidence: 99%

“…In addition, miR-145 directly targets elements in the E1 and E2 ORFS to control genome amplification. A number of studies have examined miRNA expression in HPV-positive cell lines (18,20,(22)(23)(24); however, there is significant variability in the spectrum of miRNAs reported to be altered, and this is likely the result of multiple miRNAs targeting the same cellular factors or pathways. In both cervical cancers and HPV-positive oropharyngeal cancers the levels of miR-424 are decreased, and this may be important for progression to malignancy (23,25).…”

mentioning

confidence: 99%

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Hong

Cheng

Songock

et al. 2017

J Virol

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High-risk human papillomaviruses (HPVs) link their life cycle to epithelial differentiation and require activation of DNA damage pathways for efficient replication. HPVs modulate the expression of cellular transcription factors, as well as cellular microRNAs (miRNAs) to control these activities. One miRNA that has been reported to be repressed in HPV-positive cancers of the cervix and oropharynx is miR-424. Our studies show that miR-424 levels are suppressed in cell lines that stably maintain HPV 31 or 16 episomes, as well as cervical cancer lines that contain integrated genomes such as SiHa. Introduction of expression vectors for miR-424 reduced both the levels of HPV genomes in undifferentiated cells and amplification upon differentiation. Our studies show that the levels of two putative targets of miR-424 that function in DNA damage repair, CHK1 and Wee1, are suppressed in HPV-positive cells, providing an explanation for why this microRNA is targeted in HPV-positive cells.IMPORTANCE We describe here for the first time a critical role for miR-424 in the regulation of HPV replication. HPV E6 and E7 proteins suppress the levels of miR-424, and this is important for controlling the levels of CHK1, which plays a central role in viral replication.KEYWORDS amplification, HPV, microRNA, DNA damage repair, CHK1, check point H uman papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers (1). HPVs are classified as either high-risk types (such as HPV16, -18, -31, and -35), which are associated with the development of cancers of the anogenital tract and oropharynx or low-risk groups (such as HPV6 and HPV11) that are infrequently detected in malignancies. HPV virions infect cells in the basal layer of stratified epithelia to establish persistent infections. In infected basal cell cells, genomes are maintained as low-copy episomes that replicate in synchrony with cellular chromosomes. Productive viral replication or amplification, however, occurs only upon epithelial differentiation in suprabasal layers (2, 3). High-risk HPVs encode two major oncoproteins, E6 and E7, that play critical roles in cell transformation and provide important regulatory functions during the differentiation-dependent life cycle. One major target of E6 is the E3 ligase E6-associated protein E6AP, which forms trimeric complexes with p53, resulting in its rapid turnover (4-6). Similarly, E7 binds and induces the degradation of pRb, which results in the constitutive activation of E2F family members, leading to altered cell cycle control and differentiation (7,8). Additional important targets of these viral proteins include the ataxia telangiectasia-mutated (ATM) and the ATM and Rad3-related (ATR) DNA repair pathways that play critical roles in HPV replication (9, 10). E6 and E7 regulate these pathways by altering the expression

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Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Cited by 61 publications

References 66 publications

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs

Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

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