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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 63101

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Special Issue Editor

Prof. Dr. Matthias Dürst

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Guest Editor

Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena, 07747 Jena, Germany
Interests: cervical cancer; cervical intraepithelial lesion; HPV; carcinogenesis; natural history; screening; molecular mechanism; molecular biomarkers; genetic instability; integration; next generation sequencing; vaccination

Special Issue Information

Dear Colleagues,

Cervical cancer is the fourth most common cancer in women worldwide. In contrast to most cancers it affects young women with a peak incidence at the age of 40-44 years and as such the consequences for the affected young families are particularly devastating. A prerequisite for cervical cancer is a persistent infection with a high-risk (hr) HPV type of which HPV16 has the highest prevalence among cervical cancer and precursor lesions. Most women acquire one or more hrHPV infections during their lifetime. However, most of these infections are subclinical and resolve spontaneously within several months. This clearly indicates that host and viral factors play a decisive role at all stages of disease progression. Since the discovery of HPV16 and HPV18 in the early 1980s a wealth of studies has contributed to our understanding of the natural history of HPV-infection, the molecular mechanisms of HPV-mediated carcinogenesis, epidemiological aspects, implementation of HPV in primary cancer screening programs and the impact of prophylactic and therapeutic vaccination.

Despite this enormous progress in knowledge the puzzle is by far not complete. Moreover, the use of new technologies not only consolidates and expands on our current knowledge but also raise controversial issues. In this Special Issue on “Cervical Cancer” all contributions related to the aforementioned topics, either as original paper or in form of a review, are highly welcome.

Prof. Dr. Matthias Dürst
Guest Editor

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Keywords

cervical cancer
cervical intraepithelial lesion
HPV
carcinogenesis
natural history
screening
molecular mechanism
molecular biomarkers
genetic instability
integration
next generation sequencing
vaccination

Published Papers (13 papers)

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15 pages, 2023 KiB

Open AccessArticle

HPV Infection Significantly Accelerates Glycogen Metabolism in Cervical Cells with Large Nuclei: Raman Microscopic Study with Subcellular Resolution

by Katarzyna Sitarz, Krzysztof Czamara, Joanna Bialecka, Malgorzata Klimek, Barbara Zawilinska, Slawa Szostek and Agnieszka Kaczor

Int. J. Mol. Sci. 2020, 21(8), 2667; https://doi.org/10.3390/ijms21082667 - 11 Apr 2020

Cited by 14 | Viewed by 3933

Abstract

Using Raman microscopy, we investigated epithelial cervical cells collected from 96 women with squamous cell carcinoma (SCC) or belonging to groups I, IIa, IIID-1 and IIID-2 according to Munich III classification (IIID-1 and IIID-2 corresponding to Bethesda LSIL and HSIL groups, respectively). All women were tested for human papillomavirus (HPV) infection using PCR. Subcellular resolution of Raman microscopy enabled to understand phenotypic differences in a heterogeneous population of cervical cells in the following groups: I/HPV⁻, IIa/HPV⁻, IIa/HPV⁻, LSIL/HPV⁻, LSIL/HPV⁺, HSIL/HPV⁻, HSIL/HPV⁺ and cancer cells (SCC/HPV⁺). We showed for the first time that the glycogen content in the cytoplasm decreased with the nucleus size of cervical cells in all studied groups apart from the cancer group. For the subpopulation of large-nucleus cells HPV infection resulted in considerable glycogen depletion compared to HPV negative cells in IIa, LSIL (for both statistical significance, ca. 45%) and HSIL (trend, 37%) groups. We hypothesize that accelerated glycogenolysis in large-nucleus cells may be associated with the increased protein metabolism for HPV positive cells. Our work underlines unique capabilities of Raman microscopy in single cell studies and demonstrate potential of Raman-based methods in HPV diagnostics. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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9 pages, 2094 KiB

Open AccessArticle

Differences in Stability of Viral and Viral-Cellular Fusion Transcripts in HPV-Induced Cervical Cancers

by Franziska Ehrig, Norman Häfner, Corina Driesch, Irene Kraus Christiansen, Katrin Beer, Martina Schmitz, Ingo B. Runnebaum and Matthias Dürst

Int. J. Mol. Sci. 2020, 21(1), 112; https://doi.org/10.3390/ijms21010112 - 23 Dec 2019

Cited by 4 | Viewed by 2557

Abstract

HPV-DNA integration results in dysregulation of viral oncogene expression. Because viral-cellular fusion transcripts inherently lack the viral AU-rich elements of the 3’UTR, they are considered to be more stable than episome-derived transcripts. The aim of this study is to provide formal proof for this assumption by comparing the stability of viral early transcripts derived from episomal and integrated HPV16 DNA, respectively. Full-length cDNA of three fusion transcripts comprising viral and cellular sequences in sense orientation were amplified and cloned into the adeno-viral-vector pAd/CMV/V5-DEST. The most abundant HPV16 oncogene transcript E6*I_-E7_-E1_vE4-E5 with and without 3’UTR, served as reference and control, respectively. Human primary keratinocytes were transduced using high titer virus stocks. qRT-PCR was performed to determine mRNA stability in relation to GAPDH in the presence of actinomycin-D. In four independent transduction experiments, all three viral-cellular fusion transcripts were significantly more stable compared to the episome-derived reference. Among the three viral-cellular fusion transcripts the most stable transcript was devoid of the instability core motif “AUUUA”. Unexpectedly, there was no significant difference in the stability between the episome-derived transcripts either with or without 3’UTR, indicating that the AU-rich elements of the 3’UTR are not contributing to RNA stability. Instead, the three “AUUUA” motifs located in the untranslated region between the viral E4 and E5 genes may be responsible for the instability. This is the first report showing that authentic viral-cellular fusion transcripts are more stable than episome-derived transcripts. The longer half-life of the fusion transcripts may result in increased levels of viral oncoproteins and thereby drive the carcinogenic process. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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18 pages, 9001 KiB

Open AccessArticle

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

by N. Sanjib Banerjee, Dianne Moore, Cameron J. Parker, Thomas R. Broker and Louise T. Chow

Int. J. Mol. Sci. 2019, 20(21), 5455; https://doi.org/10.3390/ijms20215455 - 01 Nov 2019

Cited by 19 | Viewed by 3249

Abstract

Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90–99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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23 pages, 4364 KiB

Open AccessArticle

Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes

by Claudia Savini, Ruwen Yang, Larisa Savelyeva, Elke Göckel-Krzikalla, Agnes Hotz-Wagenblatt, Frank Westermann and Frank Rösl

Int. J. Mol. Sci. 2019, 20(5), 1100; https://doi.org/10.3390/ijms20051100 - 04 Mar 2019

Cited by 8 | Viewed by 6872

Abstract

Supplementation of micronutrients like folate is a double-edged sword in terms of their ambivalent role in cell metabolism. Although several epidemiological studies support a protective role of folate in carcinogenesis, there are also data arguing for an opposite effect. To address this issue in the context of human papillomavirus (HPV)-induced transformation, the molecular events of different folate availability on human keratinocytes immortalized by HPV16 E6 and E7 oncoproteins were examined. Several sublines were established: Control (4.5 µM folate), folate deficient (0.002 µM folate), and repleted cells (4.5 µM folate). Cells were analyzed in terms of oncogene expression, DNA damage and repair, karyotype changes, whole-genome sequencing, and transcriptomics. Here we show that folate depletion irreversibly induces DNA damage, impairment of DNA repair fidelity, and unique chromosomal alterations. Repleted cells additionally underwent growth advantage and enhanced clonogenicity, while the above mentioned impaired molecular properties became even more pronounced. Overall, it appears that a period of folate deficiency followed by repletion can shape immortalized cells toward an anomalous phenotype, thereby potentially contributing to carcinogenesis. These observations should elicit questions and inquiries for broader additional studies regarding folate fortification programs, especially in developing countries with micronutrient deficiencies and high HPV prevalence. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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17 pages, 3516 KiB

Open AccessArticle

HPV-Mediated Resistance to TNF and TRAIL Is Characterized by Global Alterations in Apoptosis Regulatory Factors, Dysregulation of Death Receptors, and Induction of ROS/RNS

by Tatiane Karen Cabeça, Alice De Mello Abreu, Rafael Andrette, Vanesca De Souza Lino, Mirian Galliote Morale, Francisco Aguayo, Lara Termini, Luisa Lina Villa, Ana Paula Lepique and Enrique Boccardo

Int. J. Mol. Sci. 2019, 20(1), 198; https://doi.org/10.3390/ijms20010198 - 08 Jan 2019

Cited by 17 | Viewed by 3900

Abstract

Persistent infection with high-risk human papilloma virus (HR-HPV) is the main risk factor for the development of invasive cervical cancer although is not sufficient to cause cervical cancer. Several host and environmental factors play a key role in cancer initiation/progression, including cytokines and other immune-response mediators. Here, we characterized the response to the individual and combined action of the pro-inflammatory cytokines tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) on HPV-transformed cells and human keratinocytes ectopically expressing E6 and E7 early proteins from different HPV types. We showed that keratinocytes expressing HPV early proteins exhibited global alterations in the expression of proteins involved in apoptosis regulation/execution, including TNF and TRAIL receptors. Besides, we provided evidence that TNF receptor 1 (TNFR1) was down-regulated and may be retained in the cytoplasm of keratinocytes expressing HPV16 oncoproteins. Finally, fluorescence analysis demonstrated that cytokine treatment induced the production and release of reactive oxygen and nitrogen species (ROS/RNS) in cells expressing HPV oncogenes. Alterations in ROS/RNS production and apoptosis regulatory factors expression in response to inflammatory mediators may favor the accumulation of genetic alterations in HPV-infected cells. Altogether, our results suggested that these events may contribute to lesion progression and cancer onset. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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15 pages, 2160 KiB

Open AccessArticle

by Wieke W. Kremer, Marjolein Van Zummeren, Daniëlle A. M. Heideman, Birgit I. Lissenberg-Witte, Peter J. F. Snijders, Renske D. M. Steenbergen, Greta Dreyer and Chris J. L. M. Meijer

Int. J. Mol. Sci. 2018, 19(11), 3297; https://doi.org/10.3390/ijms19113297 - 23 Oct 2018

Cited by 6 | Viewed by 3366

Abstract

Data on human papillomavirus (HPV) type-specific cervical cancer risk in women living with human immunodeficiency virus (WLHIV) are needed to understand HPV–HIV interaction and to inform prevention programs for this population. We assessed high-risk HPV type-specific prevalence in cervical samples from 463 WLHIV from South Africa with different underlying, histologically confirmed stages of cervical disease. Secondly, we investigated DNA hypermethylation of host cell genes ASCL1, LHX8, and ST6GALNAC5, as markers of advanced cervical disease, in relation to type-specific HPV infection. Overall, HPV prevalence was 56% and positivity increased with severity of cervical disease: from 28.0% in cervical intraepithelial neoplasia (CIN) grade 1 or less (≤CIN1) to 100% in invasive cervical cancer (ICC). HPV16 was the most prevalent type, accounting for 9.9% of HPV-positive ≤CIN1, 14.3% of CIN2, 31.7% of CIN3, and 45.5% of ICC. HPV16 was significantly more associated with ICC and CIN3 than with ≤CIN1 (adjusted for age, OR_MH 7.36 (95% CI 2.33–23.21) and 4.37 (95% CI 1.81–10.58), respectively), as opposed to non-16 high-risk HPV types. Methylation levels of ASCL1, LHX8, and ST6GALNAC5 in cervical scrapes of women with CIN3 or worse (CIN3+) associated with HPV16 were significantly higher compared with methylation levels in cervical scrapes of women with CIN3+ associated with non-16 high-risk HPV types (p-values 0.017, 0.019, and 0.026, respectively). When CIN3 and ICC were analysed separately, the same trend was observed, but the differences were not significant. Our results confirm the key role that HPV16 plays in uterine cervix carcinogenesis, and suggest that the evaluation of host cell gene methylation levels may monitor the progression of cervical neoplasms also in WLHIV. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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16 pages, 3786 KiB

Open AccessArticle

Inhibition of Tetraspanin Functions Impairs Human Papillomavirus and Cytomegalovirus Infections

by Laura A. Fast, Snježana Mikuličić, Anna Fritzen, Jonas Schwickert, Fatima Boukhallouk, Daniel Hochdorfer, Christian Sinzger, Henar Suarez, Peter N. Monk, María Yáñez-Mó, Diana Lieber and Luise Florin

Int. J. Mol. Sci. 2018, 19(10), 3007; https://doi.org/10.3390/ijms19103007 - 02 Oct 2018

Cited by 20 | Viewed by 4513

Abstract

Tetraspanins are suggested to regulate the composition of cell membrane components and control intracellular transport, which leaves them vulnerable to utilization by pathogens such as human papillomaviruses (HPV) and cytomegaloviruses (HCMV) to facilitate host cell entry and subsequent infection. In this study, by means of cellular depletion, the cluster of differentiation (CD) tetraspanins CD9, CD63, and CD151 were found to reduce HPV16 infection in HeLa cells by 50 to 80%. Moreover, we tested recombinant proteins or peptides of specific tetraspanin domains on their effect on the most oncogenic HPV type, HPV16, and HCMV. We found that the C-terminal tails of CD63 and CD151 significantly inhibited infections of both HPV16 and HCMV. Although CD9 was newly identified as a key cellular factor for HPV16 infection, the recombinant CD9 C-terminal peptide had no effect on infection. Based on the determined half-maximal inhibitory concentration (IC₅₀), we classified CD63 and CD151 C-terminal peptides as moderate to potent inhibitors of HPV16 infection in HeLa and HaCaT cells, and in EA.hy926, HFF (human foreskin fibroblast) cells, and HEC-LTT (human endothelial cell-large T antigen and telomerase) cells for HCMV, respectively. These results indicate that HPV16 and HCMV share similar cellular requirements for their entry into host cells and reveal the necessity of the cytoplasmic CD151 and CD63 C-termini in virus infections. Furthermore, this highlights the suitability of these peptides for functional investigation of tetraspanin domains and as inhibitors of pathogen infections. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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10 pages, 2298 KiB

Open AccessArticle

ZKSCAN3 Upregulation and Its Poor Clinical Outcome in Uterine Cervical Cancer

by Sun Lee, Young-Eun Cho, Joo-Young Kim and Jae-Hoon Park

Int. J. Mol. Sci. 2018, 19(10), 2859; https://doi.org/10.3390/ijms19102859 - 20 Sep 2018

Cited by 12 | Viewed by 3126

Abstract

Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3) upregulates genes encoding proteins involved in cell differentiation, proliferation and apoptosis. ZKSCAN3 has been reported to be overexpressed in several human cancers such as colorectal cancer and prostate cancer and is proposed as a candidate oncoprotein. However, the molecular mechanism by which ZKSCAN3 participates in carcinogenesis is largely unknown. Here, we evaluated ZKSCAN3 expression in uterine cervical cancers (CC) by immunohistochemistry using formalin-fixed, paraffin-embedded tissues from 126 biopsy samples from 126 patients. The clinicopathological findings were analyzed and compared with ZKSCAN3 expression levels. ZKSCAN3 was strongly overexpressed in CCs compared to adjacent non-neoplastic cervical mucosa tissues. Moreover, a gene copy number assay showed amplified ZKSCAN3 in CC samples. ZKSCAN3 overexpression was also significantly associated with poor overall survival of the patients. Overall, our findings indicate that ZKSCAN3 overexpression is a frequent event in uterine CC and is correlated with a poor clinical outcome. ZKSCAN3 could be developed as a molecular marker for prognostic prediction and early detection. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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11 pages, 239 KiB

Open AccessArticle

Clinical Evaluation of INNO-LiPA HPV Genotyping EXTRA II Assay Using the VALGENT Framework

by Lan Xu, Elizaveta Padalko, Anja Oštrbenk, Mario Poljak and Marc Arbyn

Int. J. Mol. Sci. 2018, 19(9), 2704; https://doi.org/10.3390/ijms19092704 - 11 Sep 2018

Cited by 26 | Viewed by 4269

Abstract

In this diagnostic test validation study, we assessed the clinical accuracy and HPV genotyping performance of the INNO-LiPA HPV Genotyping Extra II (INNO-LiPA) within the VALGENT-3 framework. VALGENT is designed to assess the analytical and clinical performance of HPV tests with genotyping capacity. The VALGENT-3 panel comprised 1300 consecutive cervical cell specimens enriched with 300 samples with abnormal cytology obtained from women attending the Slovenian cervical cancer screening programme. The INNO-LiPA allows type-specific detection of 32 HPV types; however, for the clinical accuracy assessment, we considered it as high-risk (hr)HPV positive when at least one of the following HPV types was present: HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, and HPV68. Clinical accuracy for detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was compared between INNO-LiPA and Hybrid Capture 2 (HC2), which is a standard comparator test for HPV tests used in cervical cancer screening. In addition, hrHPV and type-specific detection HPV types were compared between INNO-LiPA and Linear Array HPV Genotyping Test (Linear Array). The prevalence of hrHPV determined by INNO-LiPA was 17.1% (95% CI, 15.0–19.2%) in the screening population. HrHPV testing with INNO-LiPA had a sensitivity for CIN2+ of 96.9% (95% CI, 92.1–99.1%) which was non-inferior to HC2 (relative sensitivity of 1.01; 95% CI, 0.97–1.04; p_n.inf = 0.0002) and a specificity for ≤CIN1 of 85.3% (95% CI, 83.2–87.3%) which was inferior to HC2 (relative specificity of 0.95; 95% CI, 0.93–0.97; p_n.inf = 0.9998). Genotyping agreement between INNO-LiPA and Linear Array was excellent for hrHPV, HPV16, HPV18, HPV35, HPV45, HPV58 and HPV59, but good or fair for other HPV types. To conclude, INNO-LiPA demonstrated non-inferior clinical sensitivity but lower specificity compared to HC2 in addition to excellent concordance compared to Linear Array for hrHPV and some genotypes. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

15 pages, 2522 KiB

Open AccessArticle

Low P16^INK4A Expression Associated with High Expression of Cancer Stem Cell Markers Predicts Poor Prognosis in Cervical Cancer after Radiotherapy

by Hung-Chun Fu, I-Chieh Chuang, Yi-Chien Yang, Pei-Chin Chuang, Hao Lin, Yu-Che Ou, Chan-Chao Chang Chien, Hui-Shan Huang and Hong-Yo Kang

Int. J. Mol. Sci. 2018, 19(9), 2541; https://doi.org/10.3390/ijms19092541 - 27 Aug 2018

Cited by 22 | Viewed by 4000

Abstract

Previous studies have suggested that cancer stem cells (CSCs) resisted radiotherapy and chemotherapy. P16^INK4A is a biomarker for cervical carcinogenesis and reduces proliferation of stem cells. We aimed to investigate the expression and clinical significance of cyclin-dependent kinase inhibitor 2A (P16^INK4A), sex determining region Y-box 2 (SOX2), and Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) in cervical cancer treated with radiotherapy and cervical cell line models. The expressions of P16^INK4A, SOX2, and ALDH1A1 were performed by immunohistochemical staining of tumor samples from 139 cervical cancer patients with International Federation of Gynecology and Obstetrics stages Ib to IV. The staining showed high expression in 100, 107, and 13 patients with P16^INK4A (>80%), SOX2 (≥10%), and ALDH1A1 (50%), respectively. The high-P16^INK4A group had a higher five-year overall survival (OS) rate and disease-free survival (DFS) than the low-P16^INK4A group (OS: 62.0% and 35.2%, p = 0.016; DFS: 60.0% and 31.2%, p = 0.002). The low-P16^INK4A/high-SOX2 and low-P16^INK4A/high-ALDH1A1 groups had a worse five-year OS and DFS rate than the high-P16^INK4A/low-SOX2 and high-P16^INK4A/low-ALDH1A1 groups, respectively. Depletion of P16^INK4A promoted chemoresistance and radioresistance of cervical cancer cells increased the expression of SOX2 and ALDH1A1 and exhibited higher self-renewal ability. These results suggest that lower P16^INK4A expression associated with higher CSC markers predicts poor prognostic outcomes and is a promising target in patients with cervical cancer. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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Review

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18 pages, 720 KiB

Open AccessReview

The Formation and Therapeutic Update of Tumor-Associated Macrophages in Cervical Cancer

by Qun Wang, Alexander Steger, Sven Mahner, Udo Jeschke and Helene Heidegger

Int. J. Mol. Sci. 2019, 20(13), 3310; https://doi.org/10.3390/ijms20133310 - 05 Jul 2019

Cited by 24 | Viewed by 3905

Abstract

Both clinicopathological and experimental studies have suggested that tumor-associated macrophages (TAMs) play a key role in cervical cancer progression and are associated with poor prognosis in the respects of tumor cell proliferation, invasion, angiogenesis, and immunosuppression. Therefore, having a clear understanding of TAMs is essential in treating this disease. In this review, we will discuss the origins and categories of macrophages, the molecules responsible for forming and reeducating TAMs in cervical cancer (CC), the biomarkers of macrophages and the therapy development targeting TAMs in CC research. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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13 pages, 1228 KiB

Open AccessReview

PI3K/AKT/mTOR Signaling Regulates the Virus/Host Cell Crosstalk in HPV-Positive Cervical Cancer Cells

by Felicitas Bossler, Karin Hoppe-Seyler and Felix Hoppe-Seyler

Int. J. Mol. Sci. 2019, 20(9), 2188; https://doi.org/10.3390/ijms20092188 - 03 May 2019

Cited by 72 | Viewed by 12096

Abstract

Human papillomavirus (HPV)-induced cancers will remain a significant clinical challenge for decades. Thus, the development of novel treatment strategies is urgently required, which should benefit from improving our understanding of the mechanisms of HPV-induced cell transformation. This should also include analyses of hypoxic tumor cells, which represent a major problem for cancer therapy. Recent evidence indicates that the PI3K/AKT/mTOR network plays a key role for the virus/host cell crosstalk in both normoxic and hypoxic HPV-positive cancer cells. In normoxic cells, the efficacy of the senescence induction upon experimental E6/E7 repression depends on active mTORC1 signaling. Under hypoxia, however, HPV-positive cancer cells can evade senescence due to hypoxic impairment of mTORC1 signaling, albeit the cells strongly downregulate E6/E7. Hypoxic repression of E6/E7 is mediated by the AKT kinase, which is activated under hypoxia by its canonical upstream regulators mTORC2 and PI3K. This review highlights our current knowledge about the oxygen-dependent crosstalk of the PI3K/AKT/mTOR signaling circuit with the HPV oncogenes and the phenotypic state of the host cell. Moreover, since the PI3K/AKT/mTOR pathway is considered to be a promising target for anticancer therapy, we discuss clinical implications for the treatment of HPV-positive cervical and head and neck squamous cell carcinomas. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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24 pages, 1429 KiB

Open AccessReview

Papillomaviruses and Endocytic Trafficking

by Abida Siddiqa, Justyna Broniarczyk and Lawrence Banks

Int. J. Mol. Sci. 2018, 19(9), 2619; https://doi.org/10.3390/ijms19092619 - 04 Sep 2018

Cited by 25 | Viewed by 6191

Abstract

Endocytic trafficking plays a major role in transport of incoming human papillomavirus (HPVs) from plasma membrane to the trans Golgi network (TGN) and ultimately into the nucleus. During this infectious entry, several cellular sorting factors are recruited by the viral capsid protein L2, which plays a critical role in ensuring successful transport of the L2/viral DNA complex to the nucleus. Later in the infection cycle, two viral oncoproteins, E5 and E6, have also been shown to modulate different aspects of endocytic transport pathways. In this review, we highlight how HPV makes use of and perturbs normal endocytic transport pathways, firstly to achieve infectious virus entry, secondly to produce productive infection and the completion of the viral life cycle and, finally, on rare occasions, to bring about the development of malignancy. Full article

(This article belongs to the Special Issue Molecular Research on Cervical Cancer)

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