• Colorectal cancer
• Disease risk
• Etiology
• Human papillomavirus
• Mendelian randomization

• (YYXKNLJS2024010) 2020 annual funding for discipline construction, Zhongnan Hospital of Wuhan University
• (2023-YJ-041-J-005) the Beijing Bethune Public Welfare Foundation
• (D20220060) the Natural Science Foundation of Enshi Tujia and Miao Autonomous Prefecture Government

• EMT
• Fibroblasts
• Human papillomavirus
• Microenvironment
• Oropharyngeal cancer
• Stroma
• Transcriptional reprogramming

• Epidemiology
• HPV
• HPV-associated cancers
• Pathogenesis
• Prevention

• Humans
• Papillomavirus Infections/epidemiology
• Papillomavirus Infections/prevention & control
• Papillomavirus Infections/complications
• Female
• Papillomavirus Vaccines/therapeutic use
• Uterine Cervical Neoplasms/virology
• Uterine Cervical Neoplasms/prevention & control
• Uterine Cervical Neoplasms/epidemiology
• Male
• Neoplasms/virology
• Neoplasms/epidemiology
• Neoplasms/prevention & control

• ERα
• HPV
• estrogen
• human papillomavirus
• oropharyngeal cancer
• raloxifene
• stroma
• tamoxifen
• therapeutics

• Humans
• Estrogen Receptor alpha/metabolism
• Papillomavirus Infections/virology
• Papillomavirus Infections/metabolism
• Coculture Techniques
• Fibroblasts/virology
• Fibroblasts/metabolism
• Tumor Microenvironment
• Oropharyngeal Neoplasms/virology
• Oropharyngeal Neoplasms/metabolism
• Papillomaviridae/drug effects
• Papillomaviridae/physiology
• Keratinocytes/virology
• Keratinocytes/metabolism
• Stromal Cells/metabolism
• Stromal Cells/virology
• Estrogens/metabolism
• Estrogens/pharmacology
• Selective Estrogen Receptor Modulators/pharmacology
• Tamoxifen/pharmacology
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Human Papillomavirus Viruses

• 5R03DE029548-02 HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)
• One VCU Research Strategic Priorities Plan - VCU Quest award Virginia Commonwealth University (VCU)
• P30 CA016059 NCI NIH HHS
• Philips Institute Virginia Commonwealth University (VCU)
• VCU | VCU Massey Cancer Center (Massey)

• HPV
• fibroblasts
• human papillomavirus
• microenvironment
• oropharyngeal cancer
• stroma
• transformation

• P30 CA016059 NCI NIH HHS
• R03 DE029548 NIDCR NIH HHS

• R03 DE029548 NIDCR NIH HHS

• Biomimetics
• Breast cancer
• Gastric cancer
• Lung cancer
• Skin cancer
• Theranostics

• E6
• TCGA
• head and neck squamous cell carcinoma
• human papillomavirus
• intratypic variants

• Female
• Humans
• Human papillomavirus 16/genetics
• Papillomavirus Infections
• Uterine Cervical Neoplasms
• Polymorphism, Single Nucleotide
• Head and Neck Neoplasms/genetics
• North America
• Ontario
• Oncogene Proteins, Viral/genetics

• PJT-173496 CIHR

• DCAF7
• FAM117B
• FAM53C
• GLCCI1
• RNF169
• TROAP
• development
• proteomic analysis

• P20 CA264067 NCI NIH HHS
• P20 CA264068 NCI NIH HHS
• R21 HD105144 NICHD NIH HHS

• biosensors
• clinical validations
• gated nanoporous anodic alumina
• high-risk human papilloma virus
• oligonucleotides

• Humans
• Aluminum Oxide/chemistry
• Oligonucleotides
• Human Papillomavirus Viruses
• Nanopores
• Reproducibility of Results
• Papillomavirus Infections
• DNA

• Adult
• Belief
• Human papilloma virus (HPV)
• Level of knowledge
• Vaccine

• E7
• bioinformatics analysis
• human keratinocytes
• human papillomavirus
• proteomics

• Barrett’s esophagus
• cancer
• esophageal adenocarcinoma
• human papillomavirus
• infection

This study aimed to further investigate the effect of PLD1 on the biological characteristics of human cervical cancer (CC) cell line, CASKI and the potential related molecular mechanism. CRISPR/Cas9 genome editing technology was used to knock out the PLD1 gene in CASKI cells. Cell function assays were performed to evaluate the effect of PLD1 on the biological function of CASKI cells in vivo and in vitro. A PLD1‐overexpression rescue experiment in these knockout cells was performed to further confirm its function. Two PLD1‐knockout CASKI cell lines (named PC‐11 and PC‐40, which carried the ins1/del4 mutation and del1/del2/ins1 mutation, respectively), were constructed by CRISPR/Cas9. PLD1 was overexpressed in these knockout cells (named PC11‐PLD1 and PC40‐PLD1 cells), which rescued the expression of PLD1 by approximately 71.33% and 74.54%, respectively. In vivo, the cell function assay results revealed that compared with wild‐type (WT)‐CASKI cells, the ability of PC‐11 and PC‐40 cells to proliferate, invade and migrate was significantly inhibited. The expression of H‐Ras and phosphorylation of Erk1/2 (p‐Erk1/2) was decreased in PC‐11 and PC‐40 cells compared with WT‐CASKI cells. PC‐11 and PC‐40 cells could sensitize CASKI cells to cisplatin. More importantly, the proliferation, migration and invasion of PC11‐PLD1 and PC40‐PLD1 cells with PLD1 overexpression were significantly improved compared with those of the two types of PLD1 knockout cells. The sensitivity to cisplatin was decreased in PC11‐PLD1 and PC40‐PLD1 cells compared with PC‐11 and PC‐40 cells. In vivo, in the PC‐11 and PC‐40 tumour groups, tumour growth was significantly inhibited and tumour weight (0.95 ± 0.27 g and 0.66 ± 0.43 g vs. 1.59 ± 0.67 g, p = 0.0313 and 0.0108) and volume (1069.41 ± 393.84 and 1077.72 mm³ ± 815.07 vs. 2142.94 ± 577.37 mm³, p = 0.0153 and 0.0128) were significantly reduced compared to those in the WT‐CASKI group. Tumour differentiation of the PC‐11 and PC40 cells was significantly better than that of the WT‐CASKI cells. The immunohistochemistry results confirmed that the expression of H‐Ras and p‐Erk1/2 was decreased in PC‐11 and PC‐40 tumour tissues compared with WT‐CASKI tumour tissues. PLD1 promotes CC progression by activating the RAS pathway. Inhibition of PLD1 may serve as an attractive therapeutic modality for CC.

• CRISPR/Cas9 system
• PLD1
• RAS pathway
• biological characteristics
• cervical cancer

• cervical cancer
• cytokines
• estrogen
• human papillomavirus (HPV)
• metabolism
• microenvironment

• Female
• Humans
• Carcinogenesis
• Papillomaviridae/genetics
• Papillomavirus Infections/genetics
• Tumor Microenvironment
• Uterine Cervical Neoplasms/pathology

• head and neck cancer
• human papillomavirus
• immune checkpoint inhibitor
• immuno-oncology
• tumor immunology

Novel treatment options for cervical cancer are urgently required. Ciclopirox (CPX), an iron chelator, has shown promising anti-tumorigenic potential in several preclinical tumor models, including cervical cancer cells. In these cells, CPX can induce apoptosis, a form of cell death, or senescence, an irreversible cellular growth arrest. These different phenotypic outcomes may influence therapy response. Here, we show that the decision of cervical cancer cells to induce apoptosis or senescence is strongly dependent on glucose availability: CPX induces apoptosis under limited glucose availability, whereas under increased glucose supply, CPX treatment results in senescence. Further, we link the pro-apoptotic and pro-senescent activities of CPX to its capacity to block oxidative phosphorylation and to chelate iron, respectively. In addition, we show that the combined treatment of CPX and glycolysis inhibitors blocks the proliferation of cervical cancer cells in a synergistic manner. Collectively, we provide novel insights into the anti-proliferative activities of CPX in cervical cancer cells, elucidate the cellular decision between apoptosis or senescence induction, and provide a rationale to combine CPX with glycolysis inhibitors.

The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.

• apoptosis
• cervical cancer
• human papillomavirus
• senescence
• therapy

• DUSP7
• RAS pathway
• biological characteristics
• cervical cancer
• lentiviral vector
• proteomics

The success of HPV as an infectious agent lies not within its ability to cause disease, but rather in the adeptness of the virus to establish long-term persistent infection. The ability of HPV to replicate and maintain its genome in a stratified epithelium is contingent on the manipulation of many host pathways. HPVs must abrogate host anti-viral defense programs, perturb the balance of cellular proliferation and differentiation, and hijack DNA damage signaling and repair pathways to replicate viral DNA in a stratified epithelium. Together, these characteristics contribute to the ability of HPV to achieve long-term and persistent infection and to its evolutionary success as an infectious agent.

Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis.

• HPV
• cancer
• epithelium
• extrachromosomal replication
• immune evasion
• latency
• papillomavirus
• persistence
• tethering

• Animals
• DNA, Viral/genetics
• Genome, Viral
• Humans
• Papillomaviridae/genetics
• Papillomaviridae/physiology
• Papillomavirus Infections/virology
• Virus Replication

• ZIA AI000713 Intramural NIH HHS

• HPV E6/E7 modulation
• cell cycle arrest
• cervical cancer
• histone deacetylase inhibitor
• human papillomavirus apoptosis
• senescence
• tumor suppressor

• Female sex workers
• Lagos
• human Papilloma virus

The biological importance of human papillomavirus (HPV) in the field of medicine – related to cervical carcinogenesis – has been extensively reported in the last decades. For the first time, a direct correlation between cause and effect to explain a cancer development was completely achieved in medical research. Consequently, the Nobel Prize was awarded to HZ Hausen in 2008 for his efforts to understand the effects of persistent infection of oncogenic types of HPV and malignancy transformation. The aim of the present review was to summarize the principal elements of HPV characteristics and their importance in oncology.

It is established that HPV is the main etiologic agent for the development of cervical cancer. With the evolution of diagnosis and molecular biology, many tools have become essential for an early diagnosis and thereby, considerably reducing mortality. Molecular biology continues to advance and provide new perspectives with the use of reverse-transcription PCR in automation and genotyping through next-generation sequencing. This article aims to provide an overview of what is currently used in HPV diagnostic and research and future perspectives with the help of technologies such as next-generation sequencing for screening and vaccination.

• E6
• E7
• HPV
• NGS
• RT-PCR
• cervical cancer
• immunization

• E6 inhibitors
• E6 protein
• HPV
• cervical cancer
• viral oncology

• cervical cancer
• estrogen
• estrogen receptor
• head and neck cancer
• human papillomavirus
• oropharyngeal cancer

• P30 CA016059 NCI NIH HHS
• R03 DE029548 NIDCR NIH HHS

• HPV18 E6/E7
• Histone modification
• Tip60
• Transcriptional regulation
• p300

• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Epigenesis, Genetic
• HeLa Cells
• Histone Code
• Human papillomavirus 18/genetics
• Humans
• Lysine Acetyltransferase 5/genetics
• Lysine Acetyltransferase 5/metabolism
• Oncogene Proteins, Viral/genetics
• Oncogene Proteins, Viral/metabolism
• p300-CBP Transcription Factors/genetics
• p300-CBP Transcription Factors/metabolism

• MmuPV1
• head and neck cancer
• papillomavirus

Human papillomaviruses cause around 5% of all human cancers, yet there are no specific antiviral therapeutic approaches available for combatting these cancers. These cancers are currently treated with standard chemoradiation therapy (CRT). Specific antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ERα) is overexpressed in HPV+HNSCC and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combatting HPV+cancers. Here, we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that are significant risk factors in the development of cancer, and HPV accounts for approximately 5% of all worldwide cancers. Recent studies using data from The Cancer Genome Atlas (TCGA) have demonstrated that elevated levels of estrogen receptor alpha (ERα) are associated with improved survival in oropharyngeal cancers, and these elevated receptor levels were linked with human papillomavirus-positive cancers (HPV+cancers). There has been a dramatic increase in HPV-related head and neck squamous cell carcinomas (HPV+HNSCCs) over the last 2 decades, and therapeutic options for this ongoing health crisis are a priority; currently, there are no antiviral therapeutics available for combatting HPV+cancers. During our TGCA studies on head and neck cancer, we had also discovered the overexpression of ERα in HPV+cancers. Here, we demonstrate that 17β-estradiol (estrogen) attenuates the growth/cell viability of HPV+cancers in vitro, but not HPV-negative cancer cells. In addition, N/Tert-1 cells (foreskin keratinocytes immortalized with human telomerase reverse transcriptase [hTERT]) containing human papillomavirus 16 (HPV16) have elevated levels of ERα and growth sensitivity after estrogen treatment compared with parental N/Tert-1 cells. Finally, we demonstrate that there are potentially two mechanisms contributing to the attenuation of HPV+ cell growth following estrogen treatment. First, estrogen represses the viral transcriptional long control region (LCR) downregulating early gene expression, including E6/E7. Second, expression of E6 and E7 by themselves sensitizes cells to estrogen. Overall, our results support the recent proposal that estrogen could be exploited therapeutically for the treatment of HPV-positive oral cancers.

IMPORTANCE Human papillomaviruses cause around 5% of all human cancers, yet there are no specific antiviral therapeutic approaches available for combatting these cancers. These cancers are currently treated with standard chemoradiation therapy (CRT). Specific antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ERα) is overexpressed in HPV+HNSCC and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combatting HPV+cancers. Here, we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.

• HNSCC
• HPV
• cancer
• estrogen
• keratinocyte
• transcription

GLOBOCAN 2018 latest data show cervical cancer ranks fourth in morbidity and mortality among women. Many genes in cervical lesions differ in sensitivity and specificity. However, the diagnostic molecules for early cervical cancer are not very clear. This paper screens biomarkers for early molecular diagnosis of Mongolian patients with cervical cancer.

Immunohistochemical SP method was used to detect the expression of p16^INK4a and Notch1 protein in paraffin sections of 226 Mongolian patients with HPV16‐positive cervical lesions after pathological examination, and 100 of them were randomly selected by fluorescence in situ hybridization to detect hTERC gene. The HPV16‐binding human cervical cancer SiHa cell line was used to silence the expression of HPV16 E6/E7 gene by RNA interference, and the expression of p16^INK4a, Notch1, and hTERC genes and protein expression levels were detected by RT‐PCR and Western blot.

The positive expression rates of p16^INK4a, Notch1, and hTERC genes in HPV16‐positive cervical cancer, CIN‐III, CIN‐II, CIN‐I, uterine leiomyoma, and chronic cervicitis were significantly different (P < .05); the positive expression rates of the three genes were also significantly different in the same type of cervical lesions (P < .05); RNA interference can effectively inhibit HPV16 E6/E7, p16^INK4a and Notch1 gene expression, but has no effect on hTERC gene expression.

The p16^INK4a gene can be used as a biomarker for early screening of cervical cancer, and the hTERC gene can be used to confirm the clinical diagnosis of cervical cancer.

• HPV16
• Notch1 gene
• SiHa cells
• cervical cancer
• hTERC gene
• p16INK4a gene

• biomarkers of cancer stem cells
• cervical cancer
• cervical cancer stem cells
• human papillomavirus

• Barrett's esophagus
• endoscopic mucosal reseaction
• esophageal adenocarcinoma
• human papillomavirus
• radio-frequency ablation

• Papillomavirus
• anogenital cancer
• infection and cancer
• skin cancer
• transformation

• 001 World Health Organization

Cervical cancer is the fourth most common type of gynecological malignancy to affect females, worldwide. Although high-risk human papillomavirus (HR-HPV) infection is the primary etiologic agent associated with the development of cervical cancer, cancer stem cells (CSCs) also serve a prominent role in the development, metastasis, recurrence and prognosis of the disease. CSCs are a small subpopulation of cells that have the ability to self-renew and are present in the majority of tumors, including cervical cancer. Studies describing the phenotype of cervical CSCs (CCSCs) vary in their definition of the expression pattern of principal biomarkers, including Musashi-1, aldehyde dehydrogenase 1, Oct3/4, Sox2 and CD49f. However, these markers are not observed in all cancers, although several may be present in multiple tumor types. The present review describes the potential biomarkers of CSCs in cervical cancer. These CCSC biomarkers may serve as molecular targets to enhance the efficacy and reduce the side effects associated with chemotherapeutic treatment in HR-HPV-positive cervical cancer.

• biomarkers
• cervical cancer stem cells
• high-risk human papillomavirus
• transformation zone

Human papillomaviruses (HPVs) are strongly associated with the development of cervical carcinoma, and the distribution of HPV genotypes varies regionally.

To investigate the distribution characteristics of different genotypes of HPV infection in women in Wuhan, China, a total of 13 775 patients were enrolled over 2 years.

Of these, 2436 patients were infected with HPVs, and the total infection rate was 17.68%. The infection rate of high‐risk HPV (HR‐HPV) was significantly higher (13.96%) than that of single low‐risk HPV (LR‐HPV; 3.72%). Among the HR‐HPV infections, the most common genotype was HPV 52 with an infection rate of 4.23%, followed by HPVs 16, 58, 39, and 51. The most common LR‐HPV genotype was HPV 81, followed by HPVs 6, 11, and 44. Patients under the age of 25 years were found to have the highest HPV infection rate (P < .05). After the age range of 51‐55 years, a downward trend in total HPVs and HR‐HPVs was observed. The HPV infection rate for a single genotype was higher than that for multiple HPVs (P < .01), and the detection rates in summer and winter were significantly higher than those in spring and autumn.

The results demonstrate that the distribution characteristics of various HPV genotype infections are associated with region and age and may be related to season. These data could be the basis for further epidemiological analysis into the control and prevention of HPV infection in this region.

• genotype distribution
• human papillomavirus
• infection
• membrane-based flow-through hybridization technology
• surveillance

• Mastomys coucha
• NMSC
• animal models
• causality
• cutaneous papillomaviruses
• hit-and-run mechanism
• skin cancer

Infections with cutaneous papillomaviruses have been linked to cutaneous squamous cell carcinomas that arise in patients who suffer from a rare genetic disorder, epidermodysplasia verruciformis, or those who have experienced long-term, systemic immunosuppression following organ transplantation. The E6 proteins of the prototypical cutaneous human papillomavirus (HPV) 5 and HPV8 inhibit TGF-β and NOTCH signaling. The Mus musculus papillomavirus 1, MmuPV1, infects laboratory mouse strains and causes cutaneous skin warts that can progress to squamous cell carcinomas. MmuPV1 E6 shares biological and biochemical activities with HPV8 E6 including the ability to inhibit TGF-β and NOTCH signaling by binding the SMAD2/SMAD3 and MAML1 transcription factors, respectively. Inhibition of TGF-β and NOTCH signaling is linked to delayed differentiation and sustained proliferation of differentiating keratinocytes. Furthermore, the ability of MmuPV1 E6 to bind MAML1 is necessary for wart and cancer formation in experimentally infected mice. Hence, experimental MmuPV1 infection in mice will be a robust and valuable experimental system to dissect key aspects of cutaneous HPV infection, pathogenesis, and carcinogenesis.

• epidermodysplasia verruciformis
• hit-and-run carcinogenesis
• keratinocyte differentiation
• squamous cell carcinoma
• viral oncogenesis

• Immunocompetent
• Mouse papillomavirus
• Preclinical model
• Ultraviolet radiation

Preclinical infection model systems are extremely valuable tools to aid in our understanding of Human Papillomavirus (HPV) biology, disease progression, prevention, and treatments. In this context, rodent papillomaviruses and their respective infection models are useful tools but remain underutilized resources in the field of papillomavirus biology. Two rodent papillomaviruses, MnPV1, which infects the Mastomys species of multimammate rats, and MmuPV1, which infects laboratory mice, are currently the most studied rodent PVs. Both of these viruses cause malignancy in the skin and can provide attractive infection models to study the lesser understood cutaneous papillomaviruses that have been frequently associated with HPV-related skin cancers. Of these, MmuPV1 is the first reported rodent papillomavirus that can naturally infect the laboratory strain of mice. MmuPV1 is an attractive model virus to study papillomavirus pathogenesis because of the ubiquitous availability of lab mice and the fact that this mouse species is genetically modifiable. In this review, we have summarized the knowledge we have gained about PV biology from the study of rodent papillomaviruses and point out the remaining gaps that can provide new research opportunities.

• murine papillomavirus
• papillomaviruses
• preclinical models
• rodent papillomaviruses

Cervical cancer is the third most common cancer worldwide and the fourth leading cause of cancer-associated mortality in women. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) may play key roles in the carcinogenesis of different cancers; however, little is known about the mechanisms of lncRNAs and circRNAs in the progression and metastasis of cervical cancer. In this study, we explored the expression profiles of lncRNAs, circRNAs, miRNAs, and mRNAs in HPV16 (human papillomavirus genotype 16) mediated cervical squamous cell carcinoma and matched adjacent non-tumor (ATN) tissues from three patients with high-throughput RNA sequencing (RNA-seq). In total, we identified 19 lncRNAs, 99 circRNAs, 28 miRNAs, and 304 mRNAs that were commonly differentially expressed (DE) in different patients. Among the non-coding RNAs, 3 lncRNAs and 44 circRNAs are novel to our knowledge. Functional enrichment analysis showed that DE lncRNAs, miRNAs, and mRNAs were enriched in pathways crucial to cancer as well as other gene ontology (GO) terms. Furthermore, the co-expression network and function prediction suggested that all 19 DE lncRNAs could play different roles in the carcinogenesis and development of cervical cancer. The competing endogenous RNA (ceRNA) network based on DE coding and non-coding RNAs showed that each miRNA targeted a number of lncRNAs and circRNAs. The link between part of the miRNAs in the network and cervical cancer has been validated in previous studies, and these miRNAs targeted the majority of the novel non-coding RNAs, thus suggesting that these novel non-coding RNAs may be involved in cervical cancer. Taken together, our study shows that DE non-coding RNAs could be further developed as diagnostic and therapeutic biomarkers of cervical cancer. The complex ceRNA network also lays the foundation for future research of the roles of coding and non-coding RNAs in cervical cancer.

• HPV
• RNA-seq
• ceRNA
• cervical cancer
• circRNAs
• lncRNAs

Approximately 15–20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis.

• HPV
• Human papillomavirus
• cervical cancer
• epigenetics
• histone

• Cervical cancer
• HPV 16
• Human papillomavirus
• Lineage

• Microbiome
• Microbiota
• Oncovirus
• Transkingdom interactions
• Virus-associated cancer

Human papillomavirus (HPV) is the major cause of cervical cancer, a deadly threat to millions of females. The early oncogene product (E7) of the high-risk HPV16 is the primary agent associated with HPV-related cervical cancers. In order to understand how E7 contributes to the transforming activity, we investigated the structural features of the flexible N-terminal region (46 residues) of E7 by carrying out N-15 heteronuclear NMR experiments and replica exchange molecular dynamics simulations. Several NMR parameters as well as simulation ensemble structures indicate that this intrinsically disordered region of E7 contains two transient (10-20% populated) helical pre-structured motifs that overlap with important target binding moieties such as an E2F-mimic motif and a pRb-binding LXCXE segment. Presence of such target-binding motifs in HPV16 E7 provides a reasonable explanation for its promiscuous target-binding behavior associated with its transforming activity. [BMB Reports 2016; 49(8): 431-436]

• HPV subtypes
• HPV variants
• HPV16 AA
• HPV16 E6 variants
• Head and neck squamous cell carcinoma (HNSCC)
• Human papilloma virus (HPV)

The productive human papillomavirus (HPV) life cycle is tightly linked to the differentiation and cycling of keratinocytes. Deregulation of these processes and stimulation of cell proliferation by the action of viral oncoproteins and host cell factors underlies HPV-mediated carcinogenesis. Severe HPV infections characterize the wart, hypogammaglobulinemia, infection, and myelokathexis (WHIM) immunodeficiency syndrome, which is caused by gain-of-function mutations in the CXCR4 receptor for the CXCL12 chemokine, one of which is CXCR4¹⁰¹³. We investigated whether CXCR4¹⁰¹³ interferes in the HPV18 life cycle in epithelial organotypic cultures. Expression of CXCR4¹⁰¹³ promoted stabilization of HPV oncoproteins, thus disturbing cell cycle progression and proliferation at the expense of the ordered expression of the viral genes required for virus production. Conversely, blocking CXCR4¹⁰¹³ function restored virus production and limited HPV-induced carcinogenesis. Thus, CXCR4 and its potential activation by genetic alterations in the course of the carcinogenic process can be considered as an important host factor for HPV carcinogenesis.

Human papillomaviruses (HPV) are epitheliotropic tumor viruses causing mostly benign warts but that have developed strategies to establish persistent infections. Although host immune responses clear most infections, persistence of some HPV types causes ~5% of human cancers and severe pathogenesis in immunosuppressed individuals. How early events in HPV infection, determined by the interaction between viral and host proteins, might lead to viral persistence and pathogenesis is unknown. Here, we thought to investigate this issue by providing mechanistic insights into the selective susceptibility to HPV pathogenesis displayed by patients who are immunosuppressed as a consequence of mutations in the CXCR4 gene encoding for the receptor of the CXCL12 chemokine (WHIM syndrome). We previously unraveled the existence of a general interplay between the CXCL12/CXCR4 axis and HPV, which is hijacked toward cell transformation upon expression of the CXCR4 mutant. Here, using three dimensional epithelial cell cultures to analyze the HPV life cycle, we found that the CXCR4 mutant promotes cell hyperproliferation and stabilization of viral oncoprotein expression at the expense of virus production. Our results, which identify CXCR4 as an important gatekeeper of keratinocyte proliferation and as a new susceptibility factor in HPV pathogenesis, may be translated into anti-viral and anti-cancer strategies.