The Role of Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis

Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities and they function by binding to cellular regulatory molecules, thereby subverting normal cellular homeostasis. Much effort has focused on identifying protein targets of the E6 and E7 proteins, but it has been estimated that ~98% of the human transcriptome does not encode proteins. There is a growing interest in studying noncoding RNAs as biochemical targets and biological mediators of human papillomavirus (HPV) E6/E7 oncogenic activities. This review focuses on HPV E6/E7 targeting cellular long noncoding RNAs, a class of biologically versatile molecules that regulate almost every known biological process and how this may contribute to viral oncogenesis.

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Human Papillomavirus E6 Proteins Mediate Resistance to Interferon-Induced Growth Arrest through Inhibition of p53 Acetylation

Journal of Virology ◽

10.1128/jvi.00987-07 ◽

2007 ◽

Vol 81 (23) ◽

pp. 12740-12747 ◽

Cited By ~ 29

Author(s):

Christy Hebner ◽

Melanie Beglin ◽

Laimonis A. Laimins

Keyword(s):

Human Papillomavirus ◽

Human Fibroblasts ◽

Antiviral Agents ◽

Growth Arrest ◽

Physiological Role ◽

Human Keratinocytes ◽

Hpv E6 ◽

E6 And E7 ◽

E7 Proteins ◽

Mutant Forms

ABSTRACT The high-risk human papillomavirus (HPV) E6 and E7 proteins act cooperatively to mediate multiple activities in viral pathogenesis. For instance, E7 acts to increase p53 levels while E6 accelerates its rate of turnover through the binding of the cellular ubiquitin ligase E6AP. Interferons are important antiviral agents that modulate both the initial and persistent phases of viral infection. The expression of HPV type 16 E7 was found to sensitize keratinocytes to the growth-inhibitory effects of interferon, while coexpression of E6 abrogates this inhibition. Treatment of E7-expressing cells with interferon ultimately resulted in cellular senescence through a process that is dependent upon acetylation of p53 by p300/CBP at lysine 382. Cells expressing mutant forms of E6 that are unable to bind p300/CBP or bind p53 failed to block acetylation of p53 at lysine 382 and were sensitive to growth arrest by interferon. In contrast, mutant forms of E6 that are unable to bind E6AP remain resistant to the effects of interferon, demonstrating that the absolute levels of p53 are not the major determinants of this activity. Finally, p53 acetylation at lysine 382 was found not to be an essential determinant of other types of senescence such as that induced by overexpression of Ras in human fibroblasts. This study identifies an important physiological role for E6 binding to p300/CBP in blocking growth arrest of human keratinocytes in the presence of interferon and so contributes to the persistence of HPV-infected cells.

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

Journal of Virology ◽

10.1128/jvi.01712-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 10

Author(s):

Shiyuan Hong ◽

Shouqiang Cheng ◽

William Songock ◽

Jason Bodily ◽

Laimonis A. Laimins

Keyword(s):

Dna Damage ◽

Critical Role ◽

Human Papillomaviruses ◽

Expression Vectors ◽

Hpv E6 ◽

Damage Repair ◽

Undifferentiated Cells ◽

Efficient Replication ◽

E6 And E7 ◽

E7 Proteins

ABSTRACT 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.

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Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human Papillomavirus Type 11

Journal of Virology ◽

10.1128/jvi.78.5.2620-2626.2004 ◽

2004 ◽

Vol 78 (5) ◽

pp. 2620-2626 ◽

Cited By ~ 60

Author(s):

Stephen T. Oh ◽

Michelle S. Longworth ◽

Laimonis A. Laimins

Keyword(s):

Human Papillomavirus ◽

Life Cycle ◽

High Risk ◽

Translation Termination ◽

Human Keratinocytes ◽

Low Risk ◽

Hpv E6 ◽

E6 And E7 ◽

Substitution Mutations ◽

E7 Proteins

ABSTRACT Many important functions have been attributed to the high-risk human papillomavirus (HPV) E6 and E7 proteins, including binding and degradation of p53 as well as interacting with Rb proteins. In contrast, the physiological roles of the low-risk E6 and E7 proteins remain unclear. Previous studies demonstrated that the high-risk E6 and E7 proteins also play roles in the productive life cycle by facilitating the maintenance of viral episomes (J. T. Thomas, W. G. Hubert, M. N. Ruesch, and L. A. Laimins, Proc. Natl. Acad. Sci. USA 96:8449-8454, 1999). In order to determine whether low-risk E6 or E7 is similarly necessary for the stable maintenance of episomes, HPV type 11 (HPV-11) genomes that contained translation termination mutations in E6 or E7 were constructed. Upon transfection into normal human keratinocytes, genomes in which E6 function was abolished were unable to be maintained episomally. Transfection of genomes containing substitution mutations in amino acids conserved in high- and low-risk HPV types suggested that multiple protein domains are involved in this process. Examination of cells transfected with HPV-11 genomes in which E7 function was inhibited were found to exhibit a more complex phenotype. At the second passage following transfection, mutant genomes were maintained as episomes but at significantly reduced levels than in cells transfected with the wild-type HPV-11 genome. Upon further passage in culture, however, the episomal forms of these E7 mutant genomes quickly disappeared. These findings identify important new functions for the low-risk E6 and E7 proteins in the episomal maintenance of low-risk HPV-11 genomes and suggest that they may act in a manner similar to that observed for the high-risk proteins.

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

mBio ◽

10.1128/mbio.02170-16 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 30

Author(s):

Mallory E. Harden ◽

Nripesh Prasad ◽

Anthony Griffiths ◽

Karl Munger

Keyword(s):

Gene Expression ◽

High Risk ◽

Human Papillomaviruses ◽

Cancer Development ◽

Cellular Gene ◽

Hpv16 E6 ◽

Hpv E6 ◽

E6 And E7 ◽

E7 Proteins ◽

Almost All

ABSTRACT The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation. IMPORTANCE High-risk human papillomaviruses (HPVs) are the causative agents of almost all cervical cancers and many other cancers, including anal, vaginal, vulvar, penile, and oropharyngeal cancers. Despite the availability of efficacious HPV vaccines, it is critical to determine how HPVs cause cancer, as many people remain unvaccinated and the vaccine does not prevent cancer development in individuals who are already infected. Two HPV proteins, E6 and E7, are the major drivers of cancer development, and much remains to be learned about how the expression of these viral proteins reprograms infected cells, ultimately resulting in cancer development. Small, noncoding human RNAs, termed microRNAs (miRs), regulate gene expression and have been implicated in almost all human cancers, including HPV-associated cancers. Our study provides a comprehensive analysis of how E6 and E7 alter the expression of human miRs and how this potentially impacts cellular gene expression, which may contribute to cancer development.

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The Role of lncRNA in the Development of Tumors, Including Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22168427 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8427

Author(s):

Beata Smolarz ◽

Anna Zadrożna-Nowak ◽

Hanna Romanowicz

Keyword(s):

Breast Cancer ◽

Breast Carcinoma ◽

Present Article ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Regulation Of Transcription ◽

Ribonucleic Acids ◽

Detailed Review ◽

Cellular Processes

Long noncoding RNAs (lncRNAs) are the largest groups of ribonucleic acids, but, despite the increasing amount of literature data, the least understood. Given the involvement of lncRNA in basic cellular processes, especially in the regulation of transcription, the role of these noncoding molecules seems to be of great importance for the proper functioning of the organism. Studies have shown a relationship between disturbed lncRNA expression and the pathogenesis of many diseases, including cancer. The present article presents a detailed review of the latest reports and data regarding the importance of lncRNA in the development of cancers, including breast carcinoma.

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Genome-Wide Identification and Characterization of Long Noncoding RNAs Involved in Chinese Wheat Mosaic Virus Infection of Nicotiana benthamiana

Biology ◽

10.3390/biology10030232 ◽

2021 ◽

Vol 10 (3) ◽

pp. 232

Author(s):

Weiran Zheng ◽

Haichao Hu ◽

Qisen Lu ◽

Peng Jin ◽

Linna Cai ◽

...

Keyword(s):

Virus Infection ◽

Mosaic Virus ◽

Nicotiana Benthamiana ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Differentially Expressed ◽

Genome Wide ◽

Chinese Wheat

Recent studies have shown that a large number of long noncoding RNAs (lncRNAs) can regulate various biological processes in animals and plants. Although lncRNAs have been identified in many plants, they have not been reported in the model plant Nicotiana benthamiana. Particularly, the role of lncRNAs in plant virus infection remains unknown. In this study, we identified lncRNAs in N. benthamiana response to Chinese wheat mosaic virus (CWMV) infection by RNA sequencing. A total of 1175 lncRNAs, including 65 differentially expressed lncRNAs, were identified during CWMV infection. We then analyzed the functions of some of these differentially expressed lncRNAs. Interestingly, one differentially expressed lncRNA, XLOC_006393, was found to participate in CWMV infection as a precursor to microRNAs in N. benthamiana. These results suggest that lncRNAs play an important role in the regulatory network of N. benthamiana in response to CWMV infection.

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Pathogenic Role of Immune Evasion and Integration of Human Papillomavirus in Oropharyngeal Cancer

Microorganisms ◽

10.3390/microorganisms9050891 ◽

2021 ◽

Vol 9 (5) ◽

pp. 891

Author(s):

Takashi Hatano ◽

Daisuke Sano ◽

Hideaki Takahashi ◽

Nobuhiko Oridate

Keyword(s):

Human Papillomavirus ◽

Immune Evasion ◽

Oropharyngeal Cancer ◽

Current Knowledge ◽

Immune Evasion Mechanism ◽

Cell Cycle Activation ◽

Genome Integration ◽

Integration Mechanisms ◽

E6 And E7

The incidence of oropharyngeal cancer (OPC) is increasing remarkably among all head and neck cancers, mainly due to its association with the human papillomavirus (HPV). Most HPVs are eliminated by the host’s immune system; however, because HPV has developed an effective immune evasion mechanism to complete its replication cycle, a small number of HPVs are not eliminated, leading to persistent infection. Moreover, during the oncogenic process, the extrachromosomal HPV genome often becomes integrated into the host genome. Integration involves the induction and high expression of E6 and E7, leading to cell cycle activation and increased genomic instability in the host. Therefore, integration is an important event in oncogenesis, although the associated mechanism remains unclear, especially in HPV-OPC. In this review, we summarize the current knowledge on HPV-mediated carcinogenesis, with special emphasis on immune evasion and integration mechanisms, which are crucial for oncogenesis.

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The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm7110461 ◽

2018 ◽

Vol 7 (11) ◽

pp. 461 ◽

Cited By ~ 4

Author(s):

Young-Kook Kim ◽

Juhyun Song

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Glucose Dysregulation ◽

Near Future ◽

The Brain

Long noncoding RNAs (lncRNAs) are involved in diverse physiological and pathological processes by modulating gene expression. They have been found to be dysregulated in the brain and cerebrospinal fluid of patients with neurodegenerative diseases, and are considered promising therapeutic targets for treatment. Among the various neurodegenerative diseases, diabetic Alzheimer’s disease (AD) has been recently emerging as an important issue due to several unexpected reports suggesting that metabolic issues in the brain, such as insulin resistance and glucose dysregulation, could be important risk factors for AD. To facilitate understanding of the role of lncRNAs in this field, here we review recent studies on lncRNAs in AD and diabetes, and summarize them with different categories associated with the pathogenesis of the diseases including neurogenesis, synaptic dysfunction, amyloid beta accumulation, neuroinflammation, insulin resistance, and glucose dysregulation. It is essential to understand the role of lncRNAs in the pathogenesis of diabetic AD from various perspectives for therapeutic utilization of lncRNAs in the near future.

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Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms23020930 ◽

2022 ◽

Vol 23 (2) ◽

pp. 930

Author(s):

Ba Da Yun ◽

Ye Ji Choi ◽

Seung Wan Son ◽

Gabriel Adelman Cipolla ◽

Fernanda Costa Brandão Berti ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Cell Communication ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Circular Rnas ◽

Gastrointestinal Cancers ◽

Gastrointestinal Malignancies ◽

Mesenchymal Transition ◽

Novel Therapeutic Strategies

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell–cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

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