Extracellular Vesicles in Cervical Cancer and HPV Infection

Since their description, extracellular vesicles (EVs) have shown growing relevance in cancer progression. These cell structures contain and transfer molecules such as nucleic acids (including DNA and RNA), proteins, and lipids. Despite the rising information about EVs’ relationship with cancer, there is still scarce evidence about their content and function in cervical cancer. Interestingly, the composition and purposes of some cellular molecules and the expression of oncogenic proteins packaged in EVs seem modified in HPV-infected cells; and, although only the E6 oncogenic protein has been detected in exosomes from HPV-positive cells, both E6/E7 oncogenes mRNA has been identified in EVs; however, their role still needs to be clarified. Given that EVs internalizing into adjacent or distant cells could modify their cellular behavior or promote cancer-associated events like apoptosis, proliferation, migration, or angiogenesis in receptor cells, their comprehensive study will reveal EV-associated mechanisms in cervical cancer. This review summarizes the current knowledge in composition and functions of cervical cancer and HPV Infection-derived EVs.

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microRNA Levels in Cervical Cancer Samples and Relationship with Lesion Grade and HPV Infection

MicroRNA ◽

10.2174/2211536610666210604123534 ◽

2021 ◽

Vol 10 ◽

Author(s):

Carolina R. Hoelzle ◽

Solène Arnoult ◽

Cinthya R.M. Borém ◽

Mariana Ottone ◽

Kênia C.S.F. de Magalhães ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Invasive Cervical Cancer ◽

Rna Extraction ◽

Hpv Infection ◽

Control Group ◽

Plasma Samples ◽

Cervical Lesions ◽

Dna And Rna ◽

Cervical Scraping

Background: miR-21, miR-214, and miR-let-7a are three validated and well-known miRNAs. miR-21 is described as an “oncomir,” while miR-214 and miR-let-7a are described mainly as tumor suppressors. The role of these miRNAs remains unclear in cervical cancer, an important malignancy among women worldwide and responsible for many deaths every year. Objective: The objective of this study was to describe the expression profile of miR-21, miR-214, and miR-let-7a in plasma and cervical scraping from a control group and patients with different grades of cervical lesions and invasive cervical cancer, and then correlate with HPV infection groups. Methods: Plasma and cervical scraping were submitted to DNA and RNA extraction. HPV detection and typing were performed by conventional PCR followed by PAGE to amplicons interpretation. The miRNA relative expression in plasma and cervical scraping samples was performed by real-time PCR using specific TaqMan probes. Results: miR-21 (p=0.0277) and miR-214 (p=0.0151) were up-regulated in cervical scraping samples of the invasive cervical cancer (ICC) group. However, miR-214 was also up-regulated in the LSIL group (p=0.0062). Both miRNAs were not related to HPV infection. However, miR-let-7a was higher in HPV positive plasma samples (p=0.0433) than in HPV negative plasma samples, and the correlation analysis confirmed the association between the levels of this miRNA with the presence of HPV (p=0.0407; r=0.3029), but not with lesion grade (p>0.05). Conclusion: Our results suggest that miR-21 is related to cervical cancer progression and miR-214 appears to have an ambiguous role in cervical lesions. miR-let-7a may be upregulated at the systemic level in patients with HPV infection.

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NK Cell Regulation in Cervical Cancer and Strategies for Immunotherapy

Cells ◽

10.3390/cells10113104 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3104

Author(s):

Adriana Gutiérrez-Hoya ◽

Isabel Soto-Cruz

Keyword(s):

Cervical Cancer ◽

Nk Cells ◽

Nk Cell ◽

Hpv Infection ◽

Cytolytic Activity ◽

Cellular Immunotherapy ◽

Antigen Receptors ◽

Cytokines And Chemokines ◽

Hpv Status ◽

Infected Cells

Cervical cancer is one of the most prevalent gynaecological malignancies worldwide and is related to human papillomavirus (HPV) infection, viral persistence, progression, and invasion. Therefore, the immune response is linked to HPV status. Natural killer (NK) cells play a central role against virus-infected cells and tumours through a delicate balance between activating and inhibitory receptors and secretion of cytokines and chemokines. These cells also play a crucial role in tumour immunosurveillance. For these reasons, there is growing interest in harnessing NK cells as an immunotherapy for cervical cancer. These studies are diverse and include many strategies such as transferring activated autologous or allogeneic NK cells, improving the activation and cytolytic activity of NK cells using cytokines or analogues and modifying chimeric antigen receptors to increase specificity and targeting NK cells. However, research regarding the application of NK cells in immunotherapy is limited. This article focuses on recent discoveries about using NK cells to prevent and treat cervical cancer and the possibility of cellular immunotherapy becoming one of the best strategies to exploit the immune system to fight tumours.

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Deregulation of miR-21 and miR-29a in Cervical Cancer Related to HPV Infection

MicroRNA ◽

10.2174/2211536607666181017124349 ◽

2019 ◽

Vol 8 (2) ◽

pp. 110-115 ◽

Cited By ~ 4

Author(s):

Sara Zamani ◽

Amir Sohrabi ◽

Seyed Masoud Hosseini ◽

Marjan Rahnamaye-Farzami ◽

Abolfazl Akbari

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Expression Patterns ◽

Invasive Cervical Cancer ◽

Hpv Infection ◽

Micro Rna ◽

Internal Reference ◽

Specific Primers ◽

Papilloma Virus

Background:Early diagnosis is an important factor to improve the survival of Invasive Cervical Cancer (ICC) patients. Molecular biomarkers such as micro RNA (miRNA) can be used in the early detection of ICC. The expression of miR-21 and miR-29a are deregulated in many types of human cancers.Objective:The aim of this study was to investigate the differences in miR-21 and miR-29a expression patterns in the Human Papilloma Virus (HPV) infection and various grades of cervical cancer among Iranian women.Methods:Small RNAs were extracted from positive for HPV, cervical cancer and healthy samples from 43, 50 and 46 individuals, respectively. Expression levels of miR-21 and miR-29a were analyzed by SYBR Green real-time RT-PCR using specific primers, and 5s rRNA as the internal reference gene.Results:Results have shown a significant increase in miR-21 and decrease in miR-29 in cancerous samples in comparison with the control groups (P < 0.0001).Conclusion:This study illustrated that miR-21 and miR-29a could be operated as an oncogene and tumor-suppressor in cervical cancer progression. More studies are needed to demonstrate the role of miR-21 and miR-29a as potential biomarkers for the diagnosis of cervical cancer in future investigations.

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Human papillomavirus and human telomerase RNA component gene in cervical cancer progression

Scientific Reports ◽

10.1038/s41598-019-52195-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Yang Liu ◽

Pianping Fan ◽

Yingying Yang ◽

Changjun Xu ◽

Yajuan Huang ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Progression ◽

Invasive Cervical Cancer ◽

Intraepithelial Neoplasia ◽

Hpv Infection ◽

Cancer Group ◽

Potential Marker ◽

Significant Difference ◽

Human Telomerase

Abstract This study aimed to examine hTERC gene in different grades of cervical intraepithelial neoplasia (CIN) and cervical cancer, and the association between hTERC and high risk-human papillomavirus (HR-HPV) infection. Patients who underwent cervical cancer screening at the Second Affiliated Hospital of Kunming Medical University between October 2010 and December 2011 were enrolled. All patients underwent liquid-based cytology test and hybrid capture 2 (HC2) for HPV detection. hTERC was examined using fluorescence in situ hybridization (FISH). Cervical colposcopy biopsy was performed if any of the three results was positive. HC2, FISH, and pathology were compared. A total of 1200 women underwent screening, 150 patients underwent cervical biopsy: 32 in the normal group, 38 in the CIN1 group, 66 in the CIN2/3 group, and 14 in the invasive cervical cancer group. More patients had HR-HPV infection in the CIN2/3 group and ICC group compared with the CIN1 group. hTERC increased with increasing histological dysplasia. There was significant difference in hTERC positive rate between each of the three groups. More patients with hTERC gene amplification were observed in the positive HR-HPV group than in the HR-HPV negative group. In conclusion, hTERC is a potential marker for precancerous cervical cancer lesions. hTERC might be correlated with HR-HPV infection in cervical diseases.

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Primary Cilium in Cancer Hallmarks

International Journal of Molecular Sciences ◽

10.3390/ijms20061336 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1336 ◽

Cited By ~ 17

Author(s):

Lucilla Fabbri ◽

Frédéric Bost ◽

Nathalie Mazure

Keyword(s):

Cancer Progression ◽

Primary Cilium ◽

Mammalian Cells ◽

Current Knowledge ◽

Wide Spectrum ◽

Cancer Hallmarks ◽

Mutual Regulation ◽

Ultrastructure And Function ◽

And Function ◽

External Stimuli

The primary cilium is a solitary, nonmotile and transitory appendage that is present in virtually all mammalian cells. Our knowledge of its ultrastructure and function is the result of more than fifty years of research that has dramatically changed our perspectives on the primary cilium. The mutual regulation between ciliogenesis and the cell cycle is now well-recognized, as well as the function of the primary cilium as a cellular “antenna” for perceiving external stimuli, such as light, odorants, and fluids. By displaying receptors and signaling molecules, the primary cilium is also a key coordinator of signaling pathways that converts extracellular cues into cellular responses. Given its critical tasks, any defects in primary cilium formation or function lead to a wide spectrum of diseases collectively called “ciliopathies”. An emerging role of primary cilium is in the regulation of cancer development. In this review, we seek to describe the current knowledge about the influence of the primary cilium in cancer progression, with a focus on some of the events that cancers need to face to sustain survival and growth in hypoxic microenvironment: the cancer hallmarks.

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Microbiome and Cervical Cancer

Pathobiology ◽

10.1159/000511477 ◽

2020 ◽

pp. 1-11

Author(s):

Cristina Paula Castanheira ◽

Mayara Luciana Sallas ◽

Rafaella Almeida Lima Nunes ◽

Noely Paula Cristina Lorenzi ◽

Lara Termini

Keyword(s):

Cervical Cancer ◽

Genital Tract ◽

Current Knowledge ◽

Disease Onset ◽

Female Genital Tract ◽

Hpv Infection ◽

Vaginal Microbiome ◽

Associated Lesions ◽

Cervical Disease ◽

Female Genital

Persistent infection with some types of mucosal human papillomavirus (HPV) is the etiological factor for the development of cervical cancer and its precursor lesions. Besides, several cofactors are known to play a role in cervical disease onset and progression either by favoring or by preventing HPV infection and persistence. The microbiome of a healthy female genital tract is characterized by the presence of 1 or few varieties of lactobacilli. However, high-throughput studies addressing the bacterial diversity and abundance in the female genital tract have shown that several factors, including hormonal levels, hygiene habits, and sexually transmitted diseases may disrupt the natural balance, favoring the outgrowth of some groups of bacteria, which in turn may favor some pathological states. Recently, the vaginal microbiome has emerged as a new variable that could greatly influence the natural history of HPV infections and their clinical impact. In this context, changes in the vaginal microbiome have been detected in women infected with HPV and women with HPV-associated lesions and cancer. However, the role of specific bacteria groups in the development/progression or prevention/regression of HPV-associated pathologies is not well understood. In this review we summarize the current knowledge concerning changes in vaginal microbiome and cervical disease. We discuss the potential functional interplay between specific bacterial groups and HPV infection outcomes.

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Optimisation of Folate-Mediated Liposomal Encapsulated Arsenic Trioxide for Treating HPV-Positive Cervical Cancer Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms20092156 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2156 ◽

Cited By ~ 5

Author(s):

Akhtar ◽

Ghali ◽

Wang ◽

Bell ◽

Li ◽

...

Keyword(s):

Cervical Cancer ◽

Folic Acid ◽

Cancer Cells ◽

Arsenic Trioxide ◽

Folate Receptor ◽

Hpv Infection ◽

Cytotoxicity Studies ◽

Cervical Cancer Cells ◽

Infected Cells

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO’s therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.

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Survivin Clinical Features in Cervical Cancer

Molecular and Cellular Biomedical Sciences ◽

10.21705/mcbs.v1i1.9 ◽

2017 ◽

Vol 1 (1) ◽

pp. 6

Author(s):

Miftakh Nur Rahman ◽

Chyntia Resti Wijaya ◽

Maria Novalentina

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Critical Role ◽

Survivin Expression ◽

Hpv Infection ◽

Cytotoxic T Cell ◽

Hpv E6 ◽

E6 Oncoprotein ◽

Cycle Dependent ◽

Oncogenic Protein

Cervical cancer is the primary lethal malignancy for women worldwide, but because it develops over time, it would be one of the most preventable types of cancer. Dysregulation of apoptosis in cells plays a critical role in the malignancy development. Survivin is the smallest inhibitor apoptotic protein (IAP) which has an important part in regulating cell division and inhibitor of apoptosis. This review focused on survivin features in cervical cancer from mechanisms of malignancy relationship to human papillomavirus (HPV) infection through E6 oncogenic protein, role as a biomarker in diagnosis, prognosis, staging and prediction of metastasis, and also as a target for therapy. Regulation of survivin divided into two main groups; cell cycle dependent and cell cycle independent pathway to maintain life and death balance. Survivin expression is upregulated by E6 protein simultaneously repressing p53. Thus cancerous cervical tissue developed. Survivin is also upregulated in hypoxia, a common condition in many tumors and increased angiogenesis. Survivin plays a major role in chemotherapy and radiation resistance in many cases of cervical cancer. As a target of therapy, survivin has a promising performance, suggested very specific and no issue of resistance and also reducing resistance to chemo and radiation therapy. The goal of treatment is to lower survivin expression through transcription inhibition, immunotherapy based on cytotoxic T cell (CTL) activity and gene therapy. Keywords: cervical cancer, survivin, HPV E6 oncoprotein, therapy

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Genetic predisposition for cervical cancer

Obstetrics Gynecology and Reproduction ◽

10.17749/2313-7347.139 ◽

2020 ◽

Vol 14 (2) ◽

pp. 218-228

Author(s):

T. V. Rotaru ◽

L. I. Rotaru ◽

N. P. Lapochikina

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Genetic Predisposition ◽

Antigen Processing ◽

Hpv Infection ◽

Suppressor Genes ◽

Scientific Databases ◽

Cell Mediated Immune Response ◽

Genes Encoding ◽

Altered Cell

Aim: to assess a role of genetic factors and human papillomavirus (HPV) in developing cervical neoplasia based on analyzing current publications on virus-induced carcinogenesis.Materials and methods. A systematic overview on publications dedicated to examining genetic predisposition to developing cervical cancer (CC) available in electronic databases was performed by searching in the International Scientific Databases (ISDB) PubMed/MEDLINE as well as manually by accessing enlisted input documents related to the above noted studies. Full-text publications were solely selected for analysis.Results. CC is a multifactorial disease implicating host genetic predisposition being caused by persistent high oncogenic risk HPV-infection. Immune system plays a major role in HPV-infection. Altered cell-mediated immune response is responsible for impaired potential to HPV eradication. On the other hand, immune evasion contributes to viral persistence and cancer progression. Oncogenes, cancer suppressor genes (Rb and TP53), cytokine (ILs, IFNG) and chemokine (CXCL) genes, the genes involved in antigen processing, as well as an impact for each gene polymorphism or even haplotypes playing a role in cervical carcinogenesis are mainly involved in CC developing.Conclusion. The data obtained allowed to demonstrate a role for genetic polymorphisms in the genes encoding cytokines, chemokines, diverse receptors as well as those involved in antigen processing, and cancer suppressor genes in perpetuation of HPV-infection.

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Melanoma-Derived Extracellular Vesicles: Focus on Their Proteome

Proteomes ◽

10.3390/proteomes7020021 ◽

2019 ◽

Vol 7 (2) ◽

pp. 21 ◽

Cited By ~ 8

Author(s):

Magdalena Surman ◽

Ewa Stępień ◽

Małgorzata Przybyło

Keyword(s):

Malignant Melanoma ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Potential Role ◽

Current Knowledge ◽

Extensive Investigation ◽

Disease Biomarkers ◽

Functional Studies ◽

Successful Isolation ◽

The Subject

Malignant melanoma is one of the most aggressive types of cancer, and its incidence is increasing rapidly each year. Despite the extensive research into improved diagnostic and treatment methods, early detection and disease constraint still present significant challenges. As successful isolation protocols have been developed, extracellular vesicles (EVs) have become the subject of extensive investigation in terms of their role in cancer progression and as a possible source of disease biomarkers. Besides functional studies, quantitative and qualitative proteomics have recently emerged as promising tools for the advancement of melanoma biomarkers. Nevertheless, the amount of data concerning the proteome of melanoma-derived EVs is still very limited. In this review we cover the current knowledge on protein content of melanoma-derived EVs, with a focus on their potential role in the development and progression of melanomas.

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