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Saha S, Tandon R, Sanku J, Kumari A, Shukla R, Srivastava N. siRNA-based Therapeutics in Hormone-driven Cancers: Advancements and benefits over conventional treatments. Int J Pharm 2025; 674:125463. [PMID: 40081431 DOI: 10.1016/j.ijpharm.2025.125463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
Hormone-related cancers, also known as hormone-sensitive or hormone-dependent cancers, rely on hormones such as estrogen, testosterone, and progesterone for growth. These malignancies, including breast, pituitary, thyroid, ovarian, uterine, cervical, and prostate cancers, often exhibit accelerated progression in response to hormonal signaling. Small interfering RNA (siRNA) has emerged as a groundbreaking gene suppression therapy since the FDA approval of its first product in 2018. With over 200 ongoing clinical trials, siRNA is being actively explored as a targeted treatment for hormone-related cancers. Its ability to silence specific oncogenes offers significant advantages over conventional therapies, which are often associated with toxicity, resistance, and non-specific targeting. However, challenges in siRNA delivery remain a major barrier to its clinical translation, limiting its ability to reach target cells effectively. This review evaluates the potential of siRNA in hormone-related cancers, addressing the shortcomings of traditional treatments while examining novel strategies to enhance siRNA delivery and overcome tumor microenvironment obstacles. Notably, no existing literature comprehensively consolidates siRNA-based therapies for these cancers, emphasizing the importance of this manuscript in bridging current knowledge gaps and advancing the translational application of siRNA therapeutics.
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Affiliation(s)
- Sayani Saha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Jhansi Sanku
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Anchala Kumari
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India.
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2
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Emanuelson C, Naro Y, Shade O, Liu M, Khare SD, Deiters A. Rational Design of Stapled Covalent Peptide Modifiers of Oncoprotein E6 from Human Papillomavirus. ACS Chem Biol 2025; 20:746-757. [PMID: 40063062 PMCID: PMC11934087 DOI: 10.1021/acschembio.4c00878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025]
Abstract
Human Papillomavirus (HPV) is linked to multiple cancers, most significantly cervical cancer, for which HPV infection is associated with nearly all cases. Essential to the oncogenesis of HPV is the function of the viral protein E6 and its role in degrading the cell cycle regulator p53. Degradation of p53, and the resultant loss of cell cycle control, is mediated by E6 recruitment of the E3 ubiquitin ligase E6AP and subsequent ubiquitination of p53. Here, we report the design of a stapled peptide that mimics the LxxLL α-helical domain of E6AP to bind and covalently label a cysteine residue specific to HPV-16 E6. Several acrylamide- and haloacetamide-based warheads were evaluated for reactivity and specificity, and a panel of hydrocarbon-stapled peptides was evaluated for enhanced binding affinity and increased proteolytic stability. Structure-based modeling was used to rationalize the observed trends in the reactivity of the warheads and the impact of the hydrocarbon staple position on the binding affinity of the stapled peptides. The development of a proteolytically stable and reactive peptide represents a new class of peptide-based inhibitors of protein-protein interactions with a potential therapeutic value toward HPV-derived cancers.
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Affiliation(s)
- Cole Emanuelson
- Department
of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Yuta Naro
- Department
of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Olivia Shade
- Department
of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Melinda Liu
- Department
of Chemistry and Chemical Biology, Rutgers
University, Piscataway, New Jersey 08854, United States
| | - Sagar D. Khare
- Department
of Chemistry and Chemical Biology, Rutgers
University, Piscataway, New Jersey 08854, United States
| | - Alexander Deiters
- Department
of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
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Sebutsoe XM, Tsotetsi NJN, Jantjies ZE, Raphela-Choma PP, Choene MS, Motadi LR. Therapeutic Strategies in Advanced Cervical Cancer Detection, Prevention and Treatment. Onco Targets Ther 2024; 17:785-801. [PMID: 39345275 PMCID: PMC11439348 DOI: 10.2147/ott.s475132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/08/2024] [Indexed: 10/01/2024] Open
Abstract
Cervical cancer is ranked the fourth most common cause of cancer related deaths amongst women. The situation is particularly dire in low to lower middle-income countries. It continues to affect these countries due to poor vaccine coverage and screening. Cervical cancer is mostly detected in the advanced stages leading to poor outcomes. This review focuses on the progress made to date to improve early detection and targeted therapy using both circulating RNA. Vaccine has played a major role in cervical cancer control in vaccinated young woman in mainly developed countries yet in low-income countries with challenges of 3 dose vaccination affordability, cervical cancer continues to be the second most deadly amongst women. In this review, we show the progress made in reducing cervical cancer using vaccination that in combination with other treatments that might improve survival in cervical cancer. We further show with both miRNA and siRNA that targeted therapy and specific markers might be ideal for early detection of cervical cancer in low-income countries. These markers are either upregulated or down regulated in cancer providing clue to the stage of the cancer.
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Affiliation(s)
- Xolisiwe M Sebutsoe
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | | | - Zodwa Edith Jantjies
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Portia Pheladi Raphela-Choma
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Mpho S Choene
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
| | - Lesetja R Motadi
- Department of Biochemistry C2 Lab, University of Johannesburg, Auckland Park Kingsway Campus, Johannesburg, South Africa
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Hatefi-Shogae S, Emadi-Baygi M, Ghaedi-Heydari R. Analysis of Human Papillomavirus-Associated Cervical Cancer Differentially Expressed Genes and Identification of Prognostic Factors using Integrated Bioinformatics Approaches. Adv Biomed Res 2024; 13:78. [PMID: 39512411 PMCID: PMC11542694 DOI: 10.4103/abr.abr_338_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/05/2023] [Accepted: 12/09/2023] [Indexed: 11/15/2024] Open
Abstract
Background Human papillomavirus (HPV)-induced cervical cancer progresses through a series of steps. Despite our limited understanding of the mechanisms driving this progression, identifying the key genes involved could significantly improve early detection and treatment. Materials and Methods Two gene expression profiles of GSE9750 and GSE6791, which included cervical cancer HPV-positive and -negative samples, were evaluated using the R limma package with established cut-off criteria of P value < 0.05 and | fold change| ≥ 1. KEGG pathway enrichment was performed to identify potential pathways. Weighted gene co-expression network analysis (WGCNA) was used to discover co-expressed gene modules and trait-module connections. Results Considering the defined criteria, 115 differentially expressed genes (DEGs) were identified. The DEG's KEGG pathway enrichment analysis revealed enrichment in highly relevant pathways to the HPV infection, including cell cycle, viral carcinogenesis, autophagy-animal, Epstein-Barr virus infection, human T-cell leukemia virus 1 infection, and microRNAs in cancer. WGCNA results in 13 co-expression modules, and the magenta module is identified with significant relations to HPV, cervical cancer stage, and metastasis traits. The survival analysis identified BEX1 and CDC45 as potential prognostic factors in HPV-associated cervical cancer. Conclusion The innovation of our work lies in identifying essential genes associated with the multi-step process of cervical carcinogenesis. In fact, the current study has the potential to give a distinct viewpoint on the molecular pathways linked to cervical cancer. Considering the potential importance of the hub genes, we recommend conducting in-depth wet lab research to determine their impact on the biological mechanisms of cervical cancer.
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Affiliation(s)
- Saba Hatefi-Shogae
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Modjtaba Emadi-Baygi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Rasoul Ghaedi-Heydari
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
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Lopes-Nunes J, Oliveira PA, Cruz C. Nanotherapy for human papillomavirus-associated cancers: breakthroughs and challenges. Trends Pharmacol Sci 2024; 45:781-797. [PMID: 39181737 DOI: 10.1016/j.tips.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/18/2024] [Accepted: 07/18/2024] [Indexed: 08/27/2024]
Abstract
Human papillomaviruses (HPVs) are well-known causative agents of several cancers, yet selective therapies remain under investigation. Nanoparticles, for instance, are emerging as promising solutions to enhance the delivery and efficacy of therapeutic approaches. Despite the increasing number of nanotherapies offering advantages over current treatments, only one has advanced to clinical trials. This review highlights recent advances in nanotherapies for HPV-associated cancers, focusing on the delivery of small molecules, gene-targeted therapies, and vaccines. Some of the challenges faced in nanotherapies translation for clinical application are discussed, emphasizing the most used preclinical models that fail to accurately predict human responses, thereby hindering proper evaluation of nanotherapies. Additionally, we explore and discuss alternative promising new preclinical models that could pave the way for more effective nanotherapeutic evaluations.
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Affiliation(s)
- Jéssica Lopes-Nunes
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Paula A Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building, and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Carla Cruz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; Departamento de Química, Universidade da Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001, Covilhã, Portugal.
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6
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Sisin NNT, Kong AR, Edinur HA, Jamil NIN, Che Mat NF. Silencing E6/E7 Oncoproteins in SiHa Cells Treated with siRNAs and Oroxylum indicum Extracts Induced Apoptosis by Upregulating p53/pRb Pathways. Appl Biochem Biotechnol 2024; 196:4234-4255. [PMID: 37922032 DOI: 10.1007/s12010-023-04762-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/05/2023]
Abstract
E6 and E7 human papillomavirus (HPV) oncoproteins play a significant role in the malignant transformation of infected cervical cancer cells via suppression of tumour suppressor pathways by targeting p53 and pRb, respectively. This study aimed to investigate the anticancer effects of Oroxylum indicum (OI) leaves' methanol extract on SiHa cervical cancer cells. Expression of apoptosis-related proteins (Bcl-2, caspase (cas)-3, and cas-9), viral oncoproteins (E6 and E7), and tumour suppressor proteins (p53 and pRb) were evaluated using western blot analysis before and after E6/E7 small interfering RNAs (siRNAs) transfection. In addition, the E6/E7 mRNA expression levels were assessed with real-time (RT)-PCR. The present study showed that the OI extract effectively hindered the proliferation of SiHa cells and instigated increments of cas-3 and cas-9 expressions but decreased the Bcl-2 expressions. The OI extract inhibited E6/E7 viral oncoproteins, leading to upregulation of p53 and pRb tumour suppressor genes in SiHa cells. Additionally, combinatorial treatment of OI extract and gossypin flavonoid induced restorations of p53 and pRb. Treatment with OI extract in siRNA-transfected cells also further suppressed E6/E7 expression levels and further upregulations of p53 and pRb proteins. In conclusion, OI extract treatment on siRNAs-transfected SiHa cells can additively and effectively block E6- and E7-dependent p53 and pRb degradations. All these data suggest that OI could be explored for its chemotherapeutic potential in cervical cancer cells with HPV-integrated genomes.
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Affiliation(s)
| | - Aaron Raphael Kong
- School of Health Sciences, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Hisham Atan Edinur
- School of Health Sciences, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Noor Izani Noor Jamil
- School of Health Sciences, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Nor Fazila Che Mat
- School of Health Sciences, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia.
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Sánchez-Meza LV, Bello-Rios C, Eloy JO, Gómez-Gómez Y, Leyva-Vázquez MA, Petrilli R, Bernad-Bernad MJ, Lagunas-Martínez A, Medina LA, Serrano-Bello J, Organista-Nava J, Illades-Aguiar B. Cationic Liposomes Carrying HPV16 E6-siRNA Inhibit the Proliferation, Migration, and Invasion of Cervical Cancer Cells. Pharmaceutics 2024; 16:880. [PMID: 39065577 PMCID: PMC11279637 DOI: 10.3390/pharmaceutics16070880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery systems. Modification (pegylation) with polyethylene glycol (PEG) of liposomal siRNA complexes (siRNA lipoplexes) may improve systemic stability. We studied the effect of siRNA targeting HPV16 E6, delivered via cationic liposomes (lipoplexes), on cellular processes in a cervical carcinoma cell line (CaSki) and its potential therapeutic use. Lipoplexes-PEG-HPV16 E6, composed of DOTAP, Chol, DOPE, and DSPE-PEG2000 were prepared. The results showed that pegylation (5% DSPE-PEG2000) provided stable siRNA protection, with a particle size of 86.42 ± 3.19 nm and a complexation efficiency of over 80%; the siRNA remained stable for 30 days. These lipoplexes significantly reduced HPV16 E6 protein levels and restored p53 protein expression, inhibiting carcinogenic processes such as proliferation by 25.74%, migration (95.7%), and cell invasion (97.8%) at concentrations of 20 nM, 200 nM, and 80 nM, respectively. In conclusion, cationic lipoplexes-PEG-HPV16 E6 show promise as siRNA carriers for silencing HPV16 E6 in CC.
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Affiliation(s)
- Luz Victoria Sánchez-Meza
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Ciresthel Bello-Rios
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Josimar O. Eloy
- Department of Pharmacy, Dentistry and Nursing, Faculty of Pharmacy, Federal University of Ceará, 1210 Pastor Samuel Munguba Street, Fortaleza 60430-160, CE, Brazil;
| | - Yazmín Gómez-Gómez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Marco Antonio Leyva-Vázquez
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Raquel Petrilli
- Institute of Health Sciences, University of International Integration of the Afro-Brazilian Lusophony, Redenção 62790-000, CE, Brazil;
| | | | - Alfredo Lagunas-Martínez
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Morelos, Mexico;
| | - Luis Alberto Medina
- Instituto de Física, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04510, Mexico;
- Unidad de Investigación Biomédica en Cáncer INCan/UNAM, Instituto Nacional de Cancerología, Actualmente Hospital Ángeles Puebla, Ciudad de Mexico 14080, Mexico
| | - Janeth Serrano-Bello
- Facultad de Odontología, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04360, Mexico;
| | - Jorge Organista-Nava
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
| | - Berenice Illades-Aguiar
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico; (L.V.S.-M.); (C.B.-R.); (Y.G.-G.); (M.A.L.-V.)
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Patterson MR, Meijers AS, Ryder EL, Scarth JA, Evans D, Turner AL, Wasson CW, Darell JE, Theobald D, Cogan J, James CD, Wang M, Ladbury JE, Morgan IM, Samson A, Morgan EL, Macdonald A. E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574687. [PMID: 38293147 PMCID: PMC10827106 DOI: 10.1101/2024.01.08.574687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ∼5% of all human cancers worldwide, including most cervical cancer cases and a growing number of ano-genital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited proliferation in vitro , whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we show that the LASP1 SH3 domain is essential for LASP1-mediated proliferation in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulated LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrated that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival role in cervical cancer, thus identifying a potential therapeutic target in these cancers.
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9
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Letafati A, Sakhavarz T, Khosravinia MM, Ardekani OS, Sadeghifar S, Norouzi M, Naseri M, Ghaziasadi A, Jazayeri SM. Exploring the correlation between progression of human papillomavirus infection towards carcinogenesis and nutrition. Microb Pathog 2023; 183:106302. [PMID: 37567326 DOI: 10.1016/j.micpath.2023.106302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/13/2023]
Abstract
Human papillomavirus (HPV) is a common sexually transmitted virus that can lead to the development of various types of cancer. While there are vaccines available to prevent HPV infection, there is also growing interest in the role of nutrition in reducing the risk of HPV-related cancers in HPV positive patients. Diet and nutrition play a critical role in maintaining overall health and preventing various diseases. A healthy diet can strengthen the immune system, which is essential for fighting off infections, including HPV infections, and preventing the growth and spread of cancer cells. Therefore, following a healthy diet and maintaining a healthy weight are important components of HPV and cancer prevention. This article explores the current scientific evidence on the relationship between nutrition and HPV, including the impact of specific nutrients, dietary patterns, and supplements on HPV infection toward cancer progression.
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Affiliation(s)
- Arash Letafati
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Tannaz Sakhavarz
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Mohammad Mahdi Khosravinia
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Omid Salahi Ardekani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Samira Sadeghifar
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Mehdi Norouzi
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Mona Naseri
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Azam Ghaziasadi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Seyed Mohammad Jazayeri
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
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10
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Gameiro SF, Flondra KM. Human Papillomavirus-Associated Tumor Extracellular Vesicles in HPV + Tumor Microenvironments. J Clin Med 2023; 12:5668. [PMID: 37685735 PMCID: PMC10488665 DOI: 10.3390/jcm12175668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Most infections with human papillomaviruses (HPVs) are self-resolving and asymptomatic. However, some infections can lead to the development of cancer at different mucosal sites, such as the cervix and the head and neck. Head and neck cancers (HNCs) are dichotomized into HPV-positive (HPV+) or HPV-negative (HPV-) based on their respective etiologies. Notably, the tumor microenvironment (TME) of the HPV+ subtype has an immune landscape characterized with increased immune infiltration, higher levels of T cell activation, and higher levels of immunoregulatory stimuli compared to their HPV- counterparts. Both enveloped and nonenveloped viruses hijack the extracellular vesicle (EV) biogenesis pathway to deploy a "trojan horse" strategy with a pseudoviral envelope to enhance infectivity and evade inflammation. EVs derived from HPV-infected tumor cells could allow for the stealth transport of viral cargo to neighboring nonmalignant cellular populations or infiltrating immune cells within the TME. Furthermore, viral cargo or altered cellular cargo from HPV-associated tumor EVs (HPV-TEVs) could alter the functional state or biological responses of the recipient cellular populations, which could shape the distinctive HPV+ TME. This review will cover the impact of EVs released from HPV-infected cells on HPV-induced carcinogenesis, their role in shaping the distinctive HPV+ tumor microenvironment, and current efforts to develop a painless EV-based liquid biopsy for HPV+ cancers.
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Affiliation(s)
- Steven F. Gameiro
- McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Kaitlyn M. Flondra
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, London, ON N6A 5C1, Canada;
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11
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Scarth JA, Wasson CW, Patterson MR, Evans D, Barba-Moreno D, Carden H, Cassidy R, Whitehouse A, Mankouri J, Samson A, Morgan EL, Macdonald A. Exploitation of ATP-sensitive potassium ion (K ATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling. Oncogene 2023; 42:2558-2577. [PMID: 37443304 PMCID: PMC10439009 DOI: 10.1038/s41388-023-02772-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 06/13/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023]
Abstract
Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.
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Affiliation(s)
- James A Scarth
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
- Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Christopher W Wasson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
| | - Molly R Patterson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Debra Evans
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, LS9 7TF, UK
| | - Diego Barba-Moreno
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Holli Carden
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Rosa Cassidy
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Jamel Mankouri
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Adel Samson
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, LS9 7TF, UK
| | - Ethan L Morgan
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
- School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK.
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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12
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Hewavisenti RV, Arena J, Ahlenstiel CL, Sasson SC. Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk. Front Immunol 2023; 14:1112513. [PMID: 36960048 PMCID: PMC10027931 DOI: 10.3389/fimmu.2023.1112513] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/03/2023] [Indexed: 03/09/2023] Open
Abstract
Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.
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Affiliation(s)
- Rehana V. Hewavisenti
- Immunovirology and Pathogenesis Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Joshua Arena
- Immunovirology and Pathogenesis Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
- UNSW RNA Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Chantelle L. Ahlenstiel
- Immunovirology and Pathogenesis Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
- UNSW RNA Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Sarah C. Sasson
- Immunovirology and Pathogenesis Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
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13
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Suksiri P, Sansanaphongpricha K, Muangsin N, Krusong K. Development of positively-charged cycloamylose, CAQ as efficient nanodelivery system for siRNA. Biochem Eng J 2022. [DOI: 10.1016/j.bej.2022.108767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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14
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Gameiro SF, Evans AM, Mymryk JS. The tumor immune microenvironments of HPV + and HPV - head and neck cancers. WIREs Mech Dis 2022; 14:e1539. [PMID: 35030304 DOI: 10.1002/wsbm.1539] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022]
Abstract
Human papillomaviruses (HPVs) are the etiological agent of a significant, and increasing, fraction of head and neck squamous cell carcinomas (HNSCC)-a heterogenous group of malignancies in the head and neck region. HPV infection accounts for approximately 25% of all cases, with the remainder typically caused by smoking and excessive alcohol consumption. These distinct etiologies lead to profound clinical and immunological differences between HPV-positive (HPV+ ) and HPV-negative (HPV- ) HNSCC, likely related to the expression of exogenous viral antigens in the HPV+ subtype. Specifically, HPV+ HNSCC patients generally exhibit better treatment response compared to those with HPV- disease, leading to a more favorable prognosis, with lower recurrence rate, and longer overall survival time. Importantly, a plethora of studies have illustrated that the tumor immune microenvironment (TIME) of HPV+ HNSCC has a strikingly distinct immune composition to that of its HPV- counterpart. The HPV+ TIME is characterized as being immunologically "hot," with more immune infiltration, higher levels of T-cell activation, and higher levels of immunoregulation compared to the more immunologically "cold" HPV- TIME. In general, cancers with an immune "hot" TIME exhibit better treatment response and superior clinical outcomes in comparison to their immune "cold" counterparts. Indeed, this phenomenon has also been observed in HPV+ HNSCC patients, highlighting the critical role of the TIME in influencing prognosis, and further validating the use of cancer therapies that capitalize on the mobilization and/or modulation of the TIME. This article is categorized under: Cancer > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Andris M Evans
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.,Department of Otolaryngology, The University of Western Ontario, London, Ontario, Canada.,Department of Oncology, The University of Western Ontario, London, Ontario, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada
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15
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Salinas-Montalvo AM, Supramaniam A, McMillan NA, Idris A. RNA-based gene targeting therapies for human papillomavirus driven cancers. Cancer Lett 2021; 523:111-120. [PMID: 34627949 DOI: 10.1016/j.canlet.2021.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 12/22/2022]
Abstract
While platinum-based chemotherapy, radiation therapy and or surgery are effective in reducing human papillomavirus (HPV) driven cancer tumours, they have some significant drawbacks, including low specificity for tumour, toxicity, and severe adverse effects. Though current therapies for HPV-driven cancers are effective, severe late toxicity associated with current treatments contributes to the deterioration of patient quality of life. This warrants the need for novel therapies for HPV derived cancers. In this short review, we examined RNA-based therapies targeting the major HPV oncogenes, including short-interfering RNAs (siRNAs) and clustered regularly interspaced short palindromic repeats (CRISPR) as putative treatment modalities. We also explore other potential RNA-based targeting approaches such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and mRNA vaccines as future treatment modalities for HPV cancers. Some of these technologies have already been approved for clinical use for a range of other human diseases but not for HPV cancers. Here we explore the emerging evidence supporting the effectiveness of some of these gene-based therapies for HPV malignancies. In short, the evidence sheds promising light on the feasibility of translating these technologies into a clinically relevant treatment modality for HPV derived cancers and potentially other virally driven human cancers.
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Affiliation(s)
- Ana María Salinas-Montalvo
- Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Aroon Supramaniam
- Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Nigel Aj McMillan
- Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Adi Idris
- Menzies Health Institute Queensland and School of Medical Sciences, Griffith University, Gold Coast, QLD, Australia.
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16
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Negi SS, Sharma K, Sharma D, Singh P, Agarwala P, Hussain N, Bhargava A, Das P, Agarwal S. Genetic analysis of human papilloma virus 16 E6/E7 variants obtained from cervical cancer cases in Chhattisgarh, a central state of India. Virusdisease 2021; 32:492-503. [PMID: 34631976 PMCID: PMC8473527 DOI: 10.1007/s13337-021-00727-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/11/2021] [Indexed: 11/28/2022] Open
Abstract
Human papilloma virus genotype 16 (HPV-16), a predominant etiological cause of cervical cancer (CC) vary in inflicting oncogenicity according to their geographical distribution and mutational changes. With no published data from central India, the present study aimed to genetically analyze HPV-16 E6/E7 variant obtained from CC women of Chhattisgarh. In twenty one CC patients, PCR amplified E6/E7 genes were decoded by DNA sequencing to study phylogenetic relatedness, mutational changes and their in-silico effect on protein structure. E6 analysis revealed nineteen sequences exhibited intratypic variation. L83V mutation was observed in 76.2% sequences followed by S71C seen in 28.6% sequences. Mutations of E41G, A46G, F47V, R77S, L99V and Q107K were observed in three sequences each. C140 Stop codon mutation has caused early truncation of E6 in three sequences to produce the conformational structural change. In contrast, E7 was relatively more conserved showing D4E (4.7%), G88R (23.8%), I93T (9.5%) and C94S (9.5%) mutations. Other than L83V and S71C, E6 and E7 mutations were reported for the first time from India. E6/E7 nonsynonmous mutations have a spectrum of biological effect in progression of CC. Phylogenetic analysis revealed ten sequence belonged to Asian while eleven to European sublineage to show CC cases in Chhattisgarh are a mix of Asian and European lineage. Asian sequences showing higher frequency of L83V mutations and exclusive presence of S71C and C140 Stop codon mutations may be linked with higher oncogenicity. Various E6/E7 mutational data may prove useful for development of better diagnostic and vaccine for the region of Chhattisgarh.
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Affiliation(s)
- Sanjay Singh Negi
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Kuldeep Sharma
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Divakar Sharma
- Department of Microbiology, Maulana Azad Medical College, New Delhi, 110002 India
| | - Pushpendra Singh
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Pragya Agarwala
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Nighat Hussain
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Anudita Bhargava
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Padma Das
- Department of Microbiology, AIIMS Raipur, Chhattisgarh, 492099 India
| | - Sarita Agarwal
- Department of Gynecology, AIIMS Raipur, Chhattisgarh, 492099 India
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17
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de Almeida NAA, Ribeiro CRDA, Raposo JV, de Paula VS. Immunotherapy and Gene Therapy for Oncoviruses Infections: A Review. Viruses 2021; 13:822. [PMID: 34063186 PMCID: PMC8147456 DOI: 10.3390/v13050822] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has been shown to be highly effective in some types of cancer caused by viruses. Gene therapy involves insertion or modification of a therapeutic gene, to correct for inappropriate gene products that cause/may cause diseases. Both these types of therapy have been used as alternative ways to avoid cancers caused by oncoviruses. In this review, we summarize recent studies on immunotherapy and gene therapy including the topics of oncolytic immunotherapy, immune checkpoint inhibitors, gene replacement, antisense oligonucleotides, RNA interference, clustered regularly interspaced short palindromic repeats Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based gene editing, transcription activator-like effector nucleases (TALENs) and custom treatment for Epstein-Barr virus, human T-lymphotropic virus 1, hepatitis B virus, human papillomavirus, hepatitis C virus, herpesvirus associated with Kaposi's sarcoma, Merkel cell polyomavirus, and cytomegalovirus.
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Affiliation(s)
| | | | | | - Vanessa Salete de Paula
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 21040-360 Rio de Janeiro, Brazil; (N.A.A.d.A.); (C.R.d.A.R.); (J.V.R.)
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18
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Morgan EL, Scarth JA, Patterson MR, Wasson CW, Hemingway GC, Barba-Moreno D, Macdonald A. E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer. Cell Death Differ 2021; 28:1669-1687. [PMID: 33303976 PMCID: PMC8166842 DOI: 10.1038/s41418-020-00693-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.
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Affiliation(s)
- Ethan L. Morgan
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.94365.3d0000 0001 2297 5165Present Address: Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, National Institute of Health, Bethesda, MD USA
| | - James A. Scarth
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Molly R. Patterson
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Christopher W. Wasson
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Present Address: Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, St-James University Teaching Hospital, Leeds, West Yorkshire UK
| | - Georgia C. Hemingway
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Diego Barba-Moreno
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Andrew Macdonald
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
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19
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The exon junction complex core factor eIF4A3 is a key regulator of HPV16 gene expression. Biosci Rep 2021; 41:228142. [PMID: 33760064 PMCID: PMC8026852 DOI: 10.1042/bsr20203488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/04/2021] [Accepted: 03/24/2021] [Indexed: 01/06/2023] Open
Abstract
High-risk human papillomavirus (hrHPVs), particularly HPV16 and HPV18, are the etiologic factors of ano-genital cancers and some head and neck squamous cell carcinomas (HNSCCs). Viral E6 and E7 oncoproteins, controlled at both transcriptional and post-transcriptional levels, drive hrHPVs-induced carcinogenesis. In the present study, we investigated the implication of the DEAD-box helicase eukaryotic translation initiation factor 4A3 (eIF4A3,) an Exon Junction Complex factor, in the regulation of HPV16 gene expression. Our data revealed that the depletion of the factor eIF4A3 up-regulated E7 oncoprotein levels. We also showed that the inhibition of the nonsense-mediated RNA decay (NMD) pathway, resulted in the up-regulation of E7 at both RNA and protein levels. We therefore proposed that HPV16 transcripts might present different susceptibilities to NMD and that this pathway could play a key role in the levels of expression of these viral oncoproteins during the development of HPV-related cancers.
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20
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Rahimi A, Mirzazadeh A, Tavakolpour S. Genetics and genomics of SARS-CoV-2: A review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection. Genomics 2021; 113:1221-1232. [PMID: 33007398 PMCID: PMC7525243 DOI: 10.1016/j.ygeno.2020.09.059] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/26/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
The outbreak of 2019-novel coronavirus disease (COVID-19), caused by SARS-CoV-2, started in late 2019; in a short time, it has spread rapidly all over the world. Although some possible antiviral and anti-inflammatory medications are available, thousands of people are dying daily. Well-understanding of the SARS-CoV-2 genome is not only essential for the development of new treatments/vaccines, but it also can be used for improving the sensitivity and specificity of current approaches for virus detection. Accordingly, we reviewed the most critical findings related to the genetics of the SARS-CoV-2, with a specific focus on genetic diversity and reported mutations, molecular-based diagnosis assays, using interfering RNA technology for the treatment of patients, and genetic-related vaccination strategies. Additionally, considering the unanswered questions or uncertainties in these regards, different topics were discussed.
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Affiliation(s)
- Azadeh Rahimi
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Azin Mirzazadeh
- Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Joint Bioinformatics Graduate Program, University of Arkansas Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Soheil Tavakolpour
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, United States.
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21
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Adenoviral Vectors Armed with PAPILLOMAVIRUs Oncogene Specific CRISPR/Cas9 Kill Human-Papillomavirus-Induced Cervical Cancer Cells. Cancers (Basel) 2020; 12:cancers12071934. [PMID: 32708897 PMCID: PMC7409089 DOI: 10.3390/cancers12071934] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/16/2022] Open
Abstract
Human papillomaviruses (HPV) cause malignant epithelial cancers including cervical carcinoma, non-melanoma skin and head and neck cancer. They drive tumor development through the expression of their oncoproteins E6 and E7. Designer nucleases were shown to be efficient to specifically destroy HPV16 and HPV18 oncogenes to induce cell cycle arrest and apoptosis. Here, we used high-capacity adenoviral vectors (HCAdVs) expressing the complete CRISPR/Cas9 machinery specific for HPV18-E6 or HPV16-E6. Cervical cancer cell lines SiHa and CaSki containing HPV16 and HeLa cells containing HPV18 genomes integrated into the cellular genome, as well as HPV-negative cancer cells were transduced with HPV-type-specific CRISPR-HCAdV. Upon adenoviral delivery, the expression of HPV-type-specific CRISPR/Cas9 resulted in decreased cell viability of HPV-positive cervical cancer cell lines, whereas HPV-negative cells were unaffected. Transduced cervical cancer cells showed increased apoptosis induction and decreased proliferation compared to untreated or HPV negative control cells. This suggests that HCAdV can serve as HPV-specific cancer gene therapeutic agents when armed with HPV-type-specific CRISPR/Cas9. Based on the versatility of the CRISPR/Cas9 system, we anticipate that our approach can contribute to personalized treatment options specific for the respective HPV type present in each individual tumor.
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22
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MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer. PLoS Pathog 2020; 16:e1008624. [PMID: 32555725 PMCID: PMC7326282 DOI: 10.1371/journal.ppat.1008624] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/30/2020] [Accepted: 05/13/2020] [Indexed: 12/27/2022] Open
Abstract
Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3’UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment. HPVs are the causative agents of ~5% of human cancers. Better understanding of the mechanisms by which these viruses deregulate cellular signalling pathways may offer therapeutic options for HPV-associated malignancies. The transcription factor YAP is active in cervical cancer but the mechanisms controlling its activation remain unclear. YAP is negatively regulated and sequestered in the cytoplasm through activation of the Hippo pathway. We discovered that expression of the master Hippo kinase, STK4 (also termed MST1), is reduced in HPV positive cervical cell lines and cervical disease samples. Low STK4 levels were maintained by the HPV oncogenes through up-regulation of miR-18a, which targeted the STK4 mRNA 3’UTR. Re-introduction of STK4 or bypassing miR-18a-dependent regulation de-activated YAP-driven transcription and reduced cell proliferation. Thus, our study identifies a novel interplay between HPV oncogenes and the STK4 tumour suppressor and identifies the Hippo pathway as a target for therapeutic intervention in HPV-associated malignancies.
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23
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Kumar A, Rathi E, Hariharapura RC, Kini SG. Is viral E6 oncoprotein a viable target? A critical analysis in the context of cervical cancer. Med Res Rev 2020; 40:2019-2048. [PMID: 32483862 DOI: 10.1002/med.21697] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/18/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
An understanding of the pathology of cervical cancer (CC) mediated by E6/E7 oncoproteins of high-risk human papillomavirus (HPV) was developed by late 80's. But if we look at the present scenario, not a single drug could be developed to inhibit these oncoproteins and in turn, be used specifically for the treatment of CC. The readers are advised not to presume the "viability of E6 protein" as mentioned in the title relates to just druggability of E6. The viability aspect will cover almost everything a researcher should know to develop E6 inhibitors until the preclinical stage. Herein, we have analysed the achievements and shortcomings of the scientific community in the last four decades in targeting HPV E6 against CC. Role of all HPV proteins has been briefly described for better perspective with a little detailed discussion of the role of E6. We have reviewed the articles from 1985 onward, reporting in vitro inhibition of E6. Recently, many computational studies have reported potent E6 inhibitors and these have also been reviewed. Subsequently, a critical analysis has been reported to cover the in vitro assay protocols and in vivo models to develop E6 inhibitors. A paragraph has been devoted to the role of public policy to fight CC employing vaccines and whether the vaccine against HPV has quenched the zeal to develop drugs against it. The review concludes with the challenges and the way forward.
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Affiliation(s)
- Avinash Kumar
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Ekta Rathi
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Raghu Chandrashekar Hariharapura
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Suvarna G Kini
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Rosendo-Chalma P, Antonio-Vejar V, Bigoni-Ordóñez GD, Patiño-Morales CC, Cano-García A, García-Carrancá A. CDH1 and SNAI1 are regulated by E7 from human papillomavirus types 16 and 18. Int J Oncol 2020; 57:301-313. [PMID: 32319591 DOI: 10.3892/ijo.2020.5039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 10/24/2019] [Indexed: 11/05/2022] Open
Abstract
A common characteristic of cancer types associated with viruses is the dysregulated expression of the CDH1 gene, which encodes E‑cadherin, in general by activation of DNA methyltransferases (Dnmts). In cervical cancer, E7 protein from high risk human papillomaviruses (HPVs) has been demonstrated to interact with Dnmt1 and histone deacetylase type 1 (HDAC1). The present study proposed that E7 may regulate the expression of CDH1 through two pathways: i) Epigenetic, including DNA methylation; and ii) Epigenetic‑independent, including the induction of negative regulators of CDH1 expression, such as Snail family transcriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16‑ and HPV18‑positive cell lines were used to determine the methylation pattern of the CDH1 promoter and its expression in association with its negative regulators. Different methylation frequencies were identified in the CDH1 promoter in HeLa (88.24%) compared with SiHa (17.65%) and Ca Ski (0%) cell lines. Significant differences in the expression of SNAI1 were observed between these cell lines, and an inverse association was identified between the expression levels of SNAI1 and CDH1. In addition, suppressing E7 not only increased the expression of CDH1, but notably decreased the expression of SNAI1 and modified the methylation pattern of the CDH1 promoter. These results suggested that the expression of CDH1 was dependent on the expression of SNAI1 and was inversely associated with the expression of E7. The present results indicated that E7 from HPV16/18 regulated the expression of CDH1 by the two following pathways in which Snai1 is involved: i) Hypermethylation of the CDH1 promoter region and increasing expression of SNAI1, as observed in HeLa; and ii) Hypomethylation of the CDH1 promoter region and expression of SNAI1, as observed in SiHa. Therefore, the suppression of CDH1 and expression of SNAI1 may be considered to be biomarkers of metastasis in uterine cervical cancer.
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Affiliation(s)
- Pedro Rosendo-Chalma
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autónoma de México (UNAM), Mexico City 10450, Mexico
| | - Verónica Antonio-Vejar
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Gabriele Davide Bigoni-Ordóñez
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Carlos César Patiño-Morales
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
| | - Amparo Cano-García
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC‑UAM), Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid 28029, Spain
| | - Alejandro García-Carrancá
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer of Instituto de Investigaciones Biomédicas‑Universidad Nacional Autónoma de México (IIB‑UNAM) and División de Investigación Básica of Instituto Nacional de Cancerología‑Secretaría de Salud (INCan‑SSA), Mexico City 14080, Mexico
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25
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Bharadwaj M, Hussain S, Tripathi R, Singh N, Mehrotra R. The clinico-molecular approaches for detection of human papillomavirus. Anim Biotechnol 2020. [DOI: 10.1016/b978-0-12-811710-1.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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26
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Li S, Hong X, Wei Z, Xie M, Li W, Liu G, Guo H, Yang J, Wei W, Zhang S. Ubiquitination of the HPV Oncoprotein E6 Is Critical for E6/E6AP-Mediated p53 Degradation. Front Microbiol 2019; 10:2483. [PMID: 31749782 PMCID: PMC6842930 DOI: 10.3389/fmicb.2019.02483] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/15/2019] [Indexed: 12/03/2022] Open
Abstract
High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.
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Affiliation(s)
- Siying Li
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoling Hong
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Zhentong Wei
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Min Xie
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Wanying Li
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Guanchen Liu
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, China
| | - Haoran Guo
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, China
| | - Jiaxin Yang
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, China
| | - Wei Wei
- Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, China
| | - Songling Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
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27
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Cervical cancer and HPV infection: ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins. Drug Discov Today 2019; 24:2044-2057. [DOI: 10.1016/j.drudis.2019.07.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 07/09/2019] [Accepted: 07/29/2019] [Indexed: 12/21/2022]
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28
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Duenas-Gonzalez A, Gonzalez-Fierro A. Pharmacodynamics of current and emerging treatments for cervical cancer. Expert Opin Drug Metab Toxicol 2019; 15:671-682. [DOI: 10.1080/17425255.2019.1648431] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Alfonso Duenas-Gonzalez
- Unit of Biomedical Research on Cancer, Instituto de Investigaciones Biomédicas UNAM/Instituto Nacional de Cancerología, Mexico City, Mexico
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29
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Chakravorty A, Sugden B. Long-distance communication: Looping of human papillomavirus genomes regulates expression of viral oncogenes. PLoS Biol 2018; 16:e3000062. [PMID: 30481166 PMCID: PMC6286019 DOI: 10.1371/journal.pbio.3000062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/07/2018] [Indexed: 11/18/2022] Open
Abstract
High-risk human papillomaviruses (HPVs) are a major cause of cancers. HPVs infect epithelial cells, and viral oncogenes disrupt several cellular processes, including cell division, differentiation, and apoptosis. Expression of these oncogenes is relatively low in undifferentiated epithelial cells but increases in differentiating cells by unknown mechanisms. In a new study, Parish and colleagues unveil how two cellular proteins, CCCTC-binding factor (CTCF) and Yin Yang 1 (YY1), mediate looping of the HPV18 genome, which regulates expression of viral oncogenes in both dividing and differentiating epithelial cells. This Primer explores the implications of a new study that connects viral DNA-looping and transcription of human papillomavirus oncogenes at different stages of the viral life cycle.
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Affiliation(s)
- Adityarup Chakravorty
- McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Bill Sugden
- McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- * E-mail:
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30
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Bacteria-mediated delivery of RNAi effector molecules against viral HPV16-E7 eradicates oral squamous carcinoma cells (OSCC) via apoptosis. Cancer Gene Ther 2018; 26:166-173. [DOI: 10.1038/s41417-018-0054-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/14/2018] [Indexed: 01/19/2023]
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31
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Shaikh MH, Idris A, Johnson NW, Fallaha S, Clarke DTW, Martin D, Morgan IM, Gabrielli B, McMillan NAJ. Aurora kinases are a novel therapeutic target for HPV-positive head and neck cancers. Oral Oncol 2018; 86:105-112. [PMID: 30409290 DOI: 10.1016/j.oraloncology.2018.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/30/2018] [Accepted: 09/08/2018] [Indexed: 01/22/2023]
Abstract
OBJECTIVES Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV-related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells. MATERIALS AND METHODS To assess the role of HPV E7 on HNC cell survival, RNA interference (RNAi) of the E7 gene was initially performed. Using an Aurora kinase inhibitor, Alisertib, the role of Aurora kinases in the carcinogenesis of HPV E7 positive HNC tumour lines was then investigated. An in vivo HNC xenograft model was also utilised to assess loss of tumour volume in response to RNAi E7 gene silencing and Alisertib treatment. RESULTS RNAi silencing of the HPV E7 gene inhibited the growth of HPV-positive HNC cells and in vivo tumour load. We show that HPV E7 oncogene expression confers sensitivity to Alisertib on HNC cells where Alisertib-mediated loss in in vitro cell viability and in vivo tumour load is dependent on E7 expression. Moreover, Aurora kinase inhibition induced degradation of MCL-1 in HPV E7-expressing HNC cells. CONCLUSION Overall, we show that Aurora kinases are a novel therapeutic target for HPV-positive HNCs. It might be feasible to combine Aurora kinase and MCL-1 inhibitors for future HNC therapies.
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Affiliation(s)
- Mushfiq H Shaikh
- Menzies Health Institute Queensland, School of Dentistry and Oral Health, Griffith University, Southport, Queensland, Australia; Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Adi Idris
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia; Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng City, China
| | - Newell W Johnson
- Menzies Health Institute Queensland, School of Dentistry and Oral Health, Griffith University, Southport, Queensland, Australia; Dental Institute, King's College London, London, United Kingdom
| | - Sora Fallaha
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Daniel T W Clarke
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - David Martin
- Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia; Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Iain M Morgan
- Department of Oral and Craniofacial Molecular Biology, VCU Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, VA, USA
| | - Brian Gabrielli
- Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Nigel A J McMillan
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia.
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32
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The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses. Oncogene 2018; 37:6275-6284. [PMID: 30018400 PMCID: PMC6265261 DOI: 10.1038/s41388-018-0398-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 06/08/2018] [Accepted: 06/08/2018] [Indexed: 11/08/2022]
Abstract
The skin represents a physical and chemical barrier against invading pathogens, which is additionally supported by restriction factors that provide intrinsic cellular immunity. These factors detect viruses to block their replication cycle. Here, we uncover the Myb-related transcription factor, partner of profilin (MYPOP) as a novel antiviral protein. It is highly expressed in the epithelium and binds to the minor capsid protein L2 and the DNA of human papillomaviruses (HPV), which are the primary causative agents of cervical cancer and other tumors. The early promoter activity and early gene expression of the oncogenic HPV types 16 and 18 is potently silenced by MYPOP. Cellular MYPOP-depletion relieves the restriction of HPV16 infection, demonstrating that MYPOP acts as a restriction factor. Interestingly, we found that MYPOP protein levels are significantly reduced in diverse HPV-transformed cell lines and in HPV-induced cervical cancer. Decades ago it became clear that the early oncoproteins E6 and E7 cooperate to immortalize keratinocytes by promoting degradation of tumor suppressor proteins. Our findings suggest that E7 stimulates MYPOP degradation. Moreover, overexpression of MYPOP blocks colony formation of HPV and non-virally transformed keratinocytes, suggesting that MYPOP exhibits tumor suppressor properties.
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33
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Togtema M, Jackson R, Grochowski J, Villa PL, Mellerup M, Chattopadhyaya J, Zehbe I. Synthetic siRNA targeting human papillomavirus 16 E6: a perspective on in vitro nanotherapeutic approaches. Nanomedicine (Lond) 2018; 13:455-474. [PMID: 29382252 DOI: 10.2217/nnm-2017-0242] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
High-risk human papillomaviruses infect skin and mucosa, causing approximately 5% of cancers worldwide. In the search for targeted nanotherapeutic approaches, siRNAs against the viral E6 transcript have been molecules of interest but have not yet seen successful translation into the clinic. By reviewing the past approximately 15 years of in vitro literature, we identify the need for siRNA validation protocols which concurrently evaluate ranges of key treatment parameters as well as characterize downstream process restoration in a methodical, quantitative manner and demonstrate their implementation using our own data. We also reflect on the future need for more appropriate cell culture models to represent patient lesions as well as the application of personalized approaches to identify optimal treatment strategies.
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Affiliation(s)
- Melissa Togtema
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada.,Biotechnology Program, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada
| | - Robert Jackson
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada.,Biotechnology Program, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada
| | - Jessica Grochowski
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada
| | - Peter L Villa
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada.,Department of Biology, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada
| | - Miranda Mellerup
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada
| | - Jyoti Chattopadhyaya
- Program of Chemical Biology, Institute of Cell & Molecular Biology, Uppsala University, Uppsala, SE-75123, Sweden
| | - Ingeborg Zehbe
- Probe Development & Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, ON, P7B 6V4, Canada.,Department of Biology, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada
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34
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Structural Insights in Multifunctional Papillomavirus Oncoproteins. Viruses 2018; 10:v10010037. [PMID: 29342959 PMCID: PMC5795450 DOI: 10.3390/v10010037] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 01/10/2018] [Accepted: 01/11/2018] [Indexed: 02/08/2023] Open
Abstract
Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target proteins. Here, we first summarize the diverse activities of these small multifunctional oncoproteins. Next, we review the available structural data and the new insights they provide about the evolution of E6 and E7, their multiple interactions and their functional variability across human papillomavirus (HPV) species.
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35
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Gameiro SF, Kolendowski B, Zhang A, Barrett JW, Nichols AC, Torchia J, Mymryk JS. Human papillomavirus dysregulates the cellular apparatus controlling the methylation status of H3K27 in different human cancers to consistently alter gene expression regardless of tissue of origin. Oncotarget 2017; 8:72564-72576. [PMID: 29069809 PMCID: PMC5641152 DOI: 10.18632/oncotarget.19885] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 07/03/2017] [Indexed: 12/31/2022] Open
Abstract
High-risk human papillomaviruses (HPV) cause cancer at multiple distinct anatomical locations. Regardless of the tissue of origin, most HPV positive (HPV+) cancers show highly upregulated expression of the p16 product of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene. Paradoxically, HPV+ tumor cells require continuous expression of this tumor suppressor for survival. Thus, restoration of normal p16 regulation has potential therapeutic value against HPV induced cancers. Normally, p16 transcription is tightly controlled at the epigenetic level via polycomb repressive complex-mediated tri-methylation of histone 3 lysine 27 (H3K27me3). Although a mechanism by which HPV induces p16 has been proposed based on tissue culture models, it has not been extensively validated in human tumors. In this study, we used data from over 800 human cervical and head and neck tumors from The Cancer Genome Atlas (TCGA) to test this model. We determined the impact of HPV status on expression from the CDKN2A locus, the adjacent CDKN2B locus, and transcript levels of key epigenetic regulators of these loci. As expected, HPV+ tumors from both anatomical sites exhibited high levels of p16. Furthermore, HPV+ tumors expressed higher levels of KDM6A, which demethylates H3K27me3. CpG methylation of the CDKN2A locus was also consistently altered in HPV+ tumors. This data validates previous tissue culture studies and identifies remarkable similarities between the effects of HPV on gene expression and DNA methylation in both cervical and oral tumors in large human cohorts. Furthermore, these results support a model whereby HPV-mediated dysregulation of CDKN2A transcription requires KDM6A, a potentially druggable target.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - Bart Kolendowski
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - Ali Zhang
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - John W Barrett
- Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - Anthony C Nichols
- Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON N6A 3K7, Canada.,Department of Oncology, The University of Western Ontario, London, ON N6A 3K7, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
| | - Joe Torchia
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada.,Department of Oncology, The University of Western Ontario, London, ON N6A 3K7, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 3K7, Canada.,Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON N6A 3K7, Canada.,Department of Oncology, The University of Western Ontario, London, ON N6A 3K7, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
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36
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Rolling Circle Transcription for the Self-Assembly of Multimeric RNAi Structures and Its Applications in Nanomedicine. Methods Mol Biol 2017. [PMID: 28730432 DOI: 10.1007/978-1-4939-7138-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The enzymatic process of rolling circle transcription (RCT) enables self-assembly of multimeric RNAi structures from a circular DNA template. The self-assembled RNAi structures can be manipulated easily by simple base pairing rules with short DNA fragments for constructing multifunctional nanoparticles in the field of nanomedicine. Here we describe the method to generate multifunctional RNAi nanoparticles applicable in nanomedicine.
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37
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Bahrami A, Hasanzadeh M, Hassanian SM, ShahidSales S, Ghayour-Mobarhan M, Ferns GA, Avan A. The Potential Value of the PI3K/Akt/mTOR Signaling Pathway for Assessing Prognosis in Cervical Cancer and as a Target for Therapy. J Cell Biochem 2017; 118:4163-4169. [PMID: 28475243 DOI: 10.1002/jcb.26118] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/04/2017] [Indexed: 12/31/2022]
Abstract
Cervical cancer is a common gynecological cancer and a leading cause of cancer-related death in women globally. There is a need for the identification of prognostic and predictive biomarker for risk stratification. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is often dysregulated in cervical cancer, indicating that it may be a potential therapeutic target in the treatment of this malignancy, and could perhaps be used as a novel biomarker in the assessment of risk of developing cervical cancer. We aimed to provide an overview of the potential applications of the PI3K/Akt/mTOR pathway as biomarker for risk stratification, in predicting the prognosis of cervical cancer, and for developing new therapeutic approaches in patients with cervical cancer. J. Cell. Biochem. 118: 4163-4169, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Hasanzadeh
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Gynecology Oncology, Woman Health Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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38
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Niu G, Wang D, Pei Y, Sun L. Systematic identification of key genes and pathways in the development of invasive cervical cancer. Gene 2017; 618:28-41. [PMID: 28341182 DOI: 10.1016/j.gene.2017.03.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 02/13/2017] [Accepted: 03/16/2017] [Indexed: 11/30/2022]
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Lechanteur A, Furst T, Evrard B, Delvenne P, Piel G, Hubert P. Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment. Mol Pharm 2017; 14:1706-1717. [PMID: 28350964 DOI: 10.1021/acs.molpharmaceut.6b01154] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR-HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed against the oncoprotein E6 (E6), the oncoprotein E7 (E7), or the antiapoptotic protein MCL-1 (MCL-1). The combination of siRNA anti-E7 and anti-MCL-1 demonstrated high efficacy on multiple HPV16 and HPV18 cell lines and no effects on healthy keratinocytes. This gene therapy has been considered for a vaginal administration since this route of application holds high potential for the treatment of diseases in the female reproductive tracts. Therefore, PEGylated lipoplexes have been designed and characterized to protect siRNA and to diffuse in the mucosal environment before they reach the cervico/vaginal epithelium. This new nanovector complexed to the combination of active siRNA induced an efficient mRNA knockdown since biological effects were obtained in vitro. This work also provided evidence that the PEGylated lipoplexes had appropriate physicochemical properties to diffuse into a mucin network according to size measurement experiments in artificial mucus. After demonstrating the distribution and the efficacy of siRNA into a 3D-cervical model lesion and through porcine vaginal mucosa, in vivo experiments in mouse have been performed under physiological conditions. This study revealed a complete and sustained coverage of the mucosal epithelium following an unique vaginal administration of fluorescent PEGylated lipoplexes. Overall, our results showed the potential of the PEGylated lipoplexes for the prolonged delivery of active siRNA to treat HPV-induced lesions.
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Affiliation(s)
- Anna Lechanteur
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
| | - Tania Furst
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
| | - Brigitte Evrard
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
| | - Philippe Delvenne
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
| | - Géraldine Piel
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
| | - Pascale Hubert
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège , 4000 Liège, Belgium
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40
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Yuan H, Krawczyk E, Blancato J, Albanese C, Zhou D, Wang N, Paul S, Alkhilaiwi F, Palechor-Ceron N, Dakic A, Fang S, Choudhary S, Hou TW, Zheng YL, Haddad BR, Usuda Y, Hartmann D, Symer D, Gillison M, Agarwal S, Wangsa D, Ried T, Liu X, Schlegel R. HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes. Sci Rep 2017; 7:45617. [PMID: 28378747 PMCID: PMC5381214 DOI: 10.1038/srep45617] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 03/02/2017] [Indexed: 12/23/2022] Open
Abstract
Using conditional cell reprogramming, we generated a stable cell culture of an extremely rare and aggressive neuroendocrine cervical cancer. The cultured cells contained HPV-16, formed colonies in soft agar and rapidly produced tumors in immunodeficient mice. The HPV-16 genome was integrated adjacent to the Myc gene, both of which were amplified 40-fold. Analysis of RNA transcripts detected fusion of the HPV/Myc genes, arising from apparent microhomologous recombination. Spectral karyotyping (SKY) and fluorescent-in-situ hybridization (FISH) demonstrated coordinate localization and translocation of the amplified Myc and HPV genes on chromosomes 8 and 21. Similar to the primary tumor, tumor cell cultures expressed very high levels of the Myc protein and, in contrast to all other HPV-positive cervical cancer cell lines, they harbored a gain-of-function mutation in p53 (R273C). Unexpectedly, viral oncogene knockdown had no effect on the growth of the cells, but it did inhibit the proliferation of a conventional HPV-16 positive cervical cancer cell line. Knockdown of Myc, but not the mutant p53, significantly inhibited tumor cell proliferation. On the basis of these data, we propose that the primary driver of transformation in this aggressive cervical cancer is not HPV oncogene expression but rather the overexpression of Myc.
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Affiliation(s)
- Hang Yuan
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Ewa Krawczyk
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Jan Blancato
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Christopher Albanese
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.,Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Dan Zhou
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Naidong Wang
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Siddartha Paul
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Faris Alkhilaiwi
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.,College of Pharmacy, King Abulaziz University, Jeddah, Saudi Arabia
| | - Nancy Palechor-Ceron
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Aleksandra Dakic
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Shuang Fang
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Sujata Choudhary
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Tung-Wei Hou
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Yun-Ling Zheng
- Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Bassem R Haddad
- Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Yukari Usuda
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Dan Hartmann
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - David Symer
- Human Cancer Genetics Program and Dept. of Molecular Virology, Immunology and Medical Genetics, Ohio State University Comprehensive Cancer Center, USA
| | - Maura Gillison
- Dept. of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Seema Agarwal
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Danny Wangsa
- Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Thomas Ried
- Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Xuefeng Liu
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
| | - Richard Schlegel
- Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA
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41
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Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2017; 772:23-35. [PMID: 28528687 DOI: 10.1016/j.mrrev.2016.08.001] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/18/2016] [Accepted: 08/02/2016] [Indexed: 11/17/2022]
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42
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Shaikh MH, Clarke DTW, Johnson NW, McMillan NAJ. Can gene editing and silencing technologies play a role in the treatment of head and neck cancer? Oral Oncol 2017; 68:9-19. [PMID: 28438299 DOI: 10.1016/j.oraloncology.2017.02.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 01/25/2017] [Accepted: 02/19/2017] [Indexed: 01/04/2023]
Abstract
Conventional treatment strategies have done little to improve the prognosis or disease-free survival in head and neck cancer (HNC) patients. Recent progress in our understanding of molecular aspects of head and neck squamous cell carcinoma (HNSCC) has provided insights into the potential use of molecular targeted therapies in combination with current treatment strategies. Here we review the current understanding of treatment modalities for both HPV-positive and HPV-negative HNSCCs with the potential to use gene editing and silencing technologies therapeutically. The development of sequence-specific RNA interference (RNAi) with its strong gene-specific silencing ability, high target specificity, greater potency and reduced side effects, has shown it to be a promising therapeutic candidate for treating cancers. CRISPR/Cas gene editing is the newest technology with the ability to delete, mutate or replace genes of interest and has great potential for treating HNSCCs. We also discuss the major challenge in using these approaches in HNSCC; that being the choice of target and the ability to deliver the payload. Finally, we highlight the potential combination of RNAi or CRIPSR/Cas with current treatment strategies and outline the possible path to the clinic.
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Affiliation(s)
- Mushfiq H Shaikh
- School of Dentistry and Oral Health, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia; School of Medical Science, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia; Understanding Chronic Conditions Program, Menzies Health Institute Queensland, Australia.
| | - Daniel T W Clarke
- School of Medical Science, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia; Understanding Chronic Conditions Program, Menzies Health Institute Queensland, Australia.
| | - Newell W Johnson
- School of Dentistry and Oral Health, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia; Understanding Chronic Conditions Program, Menzies Health Institute Queensland, Australia.
| | - Nigel A J McMillan
- School of Medical Science, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia; Understanding Chronic Conditions Program, Menzies Health Institute Queensland, Australia.
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43
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Zhang W, Che Q, Tan H, Qi X, Li J, Li D, Gu Q, Zhu T, Liu M. Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system. Sci Rep 2017; 7:42180. [PMID: 28176847 PMCID: PMC5296914 DOI: 10.1038/srep42180] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 01/06/2017] [Indexed: 12/26/2022] Open
Abstract
Four new antimycin alkaloids (1–4) and six related known analogs (5–10) were isolated from the culture of a marine derived Streptomyces sp. THS-55, and their structures were elucidated by extensive spectroscopic analysis. All of the compounds exhibited potent cytotoxicity in vitro against HPV-transformed HeLa cell line. Among them, compounds 6–7 were derived as natural products for the first time, and compound 5 (NADA) showed the highest potency. NADA inhibited the proliferation, arrested cell cycle distribution, and triggered apoptosis in HeLa cancer cells. Our molecular mechanic studies revealed NADA degraded the levels of E6/E7 oncoproteins through ROS-mediated ubiquitin-dependent proteasome system activation. This is the first report that demonstrates antimycin alkaloids analogue induces the degradation of high-risk HPV E6/E7 oncoproteins and finally induces apoptosis in cervical cancer cells. The present work suggested that these analogues could serve as lead compounds for the development of HPV-infected cervical cancer therapeutic agents, as well as research tools for the study of E6/E7 functions.
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Affiliation(s)
- Weiyi Zhang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China
| | - Qian Che
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Hongsheng Tan
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China
| | - Xin Qi
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Jing Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Dehai Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Qianqun Gu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Tianjiao Zhu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
| | - Ming Liu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.,Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China
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44
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SIRT1 overexpression in cervical squamous intraepithelial lesions and invasive squamous cell carcinoma. Hum Pathol 2017; 59:102-107. [DOI: 10.1016/j.humpath.2016.09.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 09/04/2016] [Accepted: 09/22/2016] [Indexed: 11/17/2022]
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45
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Egawa N, Doorbar J. The low-risk papillomaviruses. Virus Res 2016; 231:119-127. [PMID: 28040475 DOI: 10.1016/j.virusres.2016.12.017] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
Human Papillomavirus (HPV) research has been dominated by the study of a subset of Alpha papillomaviruses that together cause almost 5% of human cancers worldwide, with the focus being on the two most prominent of these (HPV16 and 18). These viruses are referred to as 'high-risk' (hrHPV), to distinguish them from the over 200 prevalent HPV types that more commonly cause only benign epithelial lesions. The 'low-risk' (lrHPV) term used to describe this group belies their cumulative morbidity. Persistent laryngeal papillomas, which occur rarely in children and adults, require regular surgical de-bulking to allow breathing. Such infections are not curable, and despite being caused by HPV11 (a lrHPV) are associated with 1-3% risk of cancer progression if not resolved. Similarly, the ubiquitous Beta HPV types, which commonly cause asymptomatic infections at cutaneous sites, can sometimes cause debilitating papillomatosis with associated cancer risk. Recalcitrant genital warts, which affect 1 in 200 young adults in the general population, and even the ubiquitous common warts and verrucas that most of us at some time experience, cannot be reliably eradicated, with treatment strategies advancing little over the last 100 years. The review highlights molecular similarities between high and low-risk HPV types, and focuses on the different pathways that the two groups use to ensure persistent infection and adequate virus shedding from the epithelial surface. Understanding the normal patterns of viral gene expression that underlie lesion formation, and which also prevent loss of the infected basal cells in established lesions, are particularly important when considering new treatment options. Finally, the common requirement for deregulated viral gene expression and genome persistence in development of cancers, unites both high and low-risk HPV types, and when considered alongside viral protein functions, provides us with a working understanding of the mechanisms that underlie HPV-associated pathology.
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Affiliation(s)
- Nagayasu Egawa
- Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, UK
| | - John Doorbar
- Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, UK.
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46
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Carr MI, Jones SN. Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis. Transl Cancer Res 2016; 5:707-724. [PMID: 28690977 PMCID: PMC5501481 DOI: 10.21037/tcr.2016.11.75] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.
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Affiliation(s)
- Michael I Carr
- Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Stephen N Jones
- Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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47
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48
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Lechanteur A, Furst T, Evrard B, Delvenne P, Hubert P, Piel G. PEGylation of lipoplexes: The right balance between cytotoxicity and siRNA effectiveness. Eur J Pharm Sci 2016; 93:493-503. [PMID: 27593989 DOI: 10.1016/j.ejps.2016.08.058] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 08/18/2016] [Accepted: 08/29/2016] [Indexed: 12/16/2022]
Abstract
The delivery of small interfering RNA (siRNA) is an attractive therapeutic approach to treat several pathologies, such as viral infections or cancers. However, the stability and the efficacy of these biotherapies are still a major obstacle to their use. Cationic liposomes (DOTAP/Chol/DOPE 1/0.75/0.5M ratio) have been complexed to siRNA (lipoplexes) in order to be administrated by the vaginal route, in the context of HPV16 induced cervical preneoplastic lesions. To overcome the constraint of the cervico-vaginal mucus, PEGylation is required to allow the diffusion of lipoplexes through it. Thereby, PEGylated lipoplexes coated with three types of polyethylene glycol (PEG) as DSPE-PEG2000, DSPE-PEG750 or C8-PEG2000-Ceramide (Ceramide-PEG2000) at different densities have been developed and characterized. PEGylated lipoplexes were successfully prepared and showed a hydrodynamic diameter around 200nm, appropriate for vaginal application. In vitro assays on HPV16 positive cell lines revealed that a positive charge of PEGylated lipoplexes allows a higher mRNA knockdown by siRNA. However, the cationic property is also associated to cytotoxicity. The addition of a high percentage of PEG prevented this toxicity but seemed also to reduce siRNA endosomal escape, probably by steric hindrance. The decreasing of PEG density of Ceramide-PEG2000 to 20% allows the release of siRNA and in consequence, biological activities, contrarily to DSPE-PEG. These results suggest that Ceramide-PEG is more appropriate for siRNA delivery compared to DSPE-PEG. In conclusion, the right balance between cytotoxicity and siRNA effectiveness has been found with the transfection of lipoplexes coated with 20% of Ceramide-PEG2000. This new nanovector could have a high potential against multiple mucosal diseases, such as human papillomavirus-induced genital lesions.
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Affiliation(s)
- Anna Lechanteur
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, University of Liège, Liège 4000, Belgium; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège 4000, Belgium.
| | - Tania Furst
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, University of Liège, Liège 4000, Belgium
| | - Brigitte Evrard
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, University of Liège, Liège 4000, Belgium
| | - Philippe Delvenne
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège 4000, Belgium
| | - Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège 4000, Belgium
| | - Géraldine Piel
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, University of Liège, Liège 4000, Belgium
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49
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Li L, Xu C, Long J, Shen D, Zhou W, Zhou Q, Yang J, Jiang M. E6 and E7 gene silencing results in decreased methylation of tumor suppressor genes and induces phenotype transformation of human cervical carcinoma cell lines. Oncotarget 2016; 6:23930-43. [PMID: 26329329 PMCID: PMC4695162 DOI: 10.18632/oncotarget.4525] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Accepted: 06/02/2015] [Indexed: 01/01/2023] Open
Abstract
In SiHa and CaSki cells, E6 and E7-targeting shRNA specifically and effectively knocked down human papillomavirus (HPV) 16 E6 and E7 at the transcriptional level, reduced the E6 and E7 mRNA levels by more than 80% compared with control cells that expressed a scrambled-sequence shRNA. E6 and E7 repression resulted in down-regulation of DNA methyltransferase mRNA and protein expression, decreased DNA methylation and increased mRNA expression levels of tumor suppressor genes, induced a certain apoptosis and inhibited proliferation in E6 and E7 shRNA-infected SiHa and CaSki cells compared with the uninfected cells. Repression of E6 and E7 oncogenes resulted in restoration of DNA methyltransferase suppressor pathways and induced apoptosis in HPV16-positive cervical carcinoma cell lines. Our findings suggest that the potential carcinogenic mechanism of HPV16 through influencing DNA methylation pathway to activate the development of cervical cancer exist, and maybe as a candidate therapeutic strategy for cervical and other HPV-associated cancers.
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Affiliation(s)
- Liming Li
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Cui Xu
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Jia Long
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Danbei Shen
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Wuqing Zhou
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Qiyan Zhou
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Jia Yang
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Mingjun Jiang
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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50
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Halec G, Schmitt M, Egger S, Abnet CC, Babb C, Dawsey SM, Flechtenmacher C, Gheit T, Hale M, Holzinger D, Malekzadeh R, Taylor PR, Tommasino M, Urban MI, Waterboer T, Pawlita M, Sitas F. Mucosal alpha-papillomaviruses are not associated with esophageal squamous cell carcinomas: Lack of mechanistic evidence from South Africa, China and Iran and from a world-wide meta-analysis. Int J Cancer 2016; 139:85-98. [PMID: 26529033 PMCID: PMC5772872 DOI: 10.1002/ijc.29911] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 10/07/2015] [Accepted: 10/15/2015] [Indexed: 12/19/2022]
Abstract
Epidemiological and mechanistic evidence on the causative role of human papillomaviruses (HPV) in esophageal squamous cell carcinoma (ESCC) is unclear. We retrieved alcohol- and formalin-fixed paraffin-embedded ESCC tissues from 133 patients seropositive for antibodies against HPV early proteins, from high-incidence ESCC regions: South Africa, China and Iran. With rigorous care to prevent nucleic acid contamination, we analyzed these tissues for the presence of 51 mucosotropic human alpha-papillomaviruses by two sensitive, broad-spectrum genotyping methods, and for the markers of HPV-transformed phenotype: (i) HPV16/18 viral loads by quantitative real-time PCR, (ii) type-specific viral mRNA by E6*I/E6 full-length RT-PCR assays and (iii) expression of cellular protein p16(INK4a). Of 118 analyzable ESCC tissues, 10 (8%) were positive for DNA of HPV types: 16 (4 tumors); 33, 35, 45 (1 tumor each); 11 (2 tumors) and 16, 70 double infection (1 tumor). Inconsistent HPV DNA+ findings by two genotyping methods and negativity in qPCR indicated very low viral loads. A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16(INK4a) negative (HPV16 E1 seropositive patient). Another HPV16 DNA+ tumor from an HPV16 E6 seropositive patient showed p16(INK4a) upregulation but no HPV16 mRNA. In the tumor tissues of these serologically preselected ESCC patients, we did not find consistent presence of HPV DNA, HPV mRNA or p16(INK4a) upregulation. These results were supported by a meta-analysis of 14 other similar studies regarding HPV-transformation of ESCC. Our study does not support the etiological role of the 51 analyzed mucosotropic HPV types in the ESCC carcinogenesis.
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Affiliation(s)
- Gordana Halec
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Obstetrics & Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Markus Schmitt
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sam Egger
- Cancer Council NSW, Cancer Research Division, Sydney, New South Wales, Australia
| | - Christian C Abnet
- Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, MD
| | - Chantal Babb
- National Health Laboratory Service, NHLS/MRC Cancer Epidemiology Research Group, Johannesburg, South Africa
| | - Sanford M Dawsey
- Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, MD
| | | | - Tarik Gheit
- Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France
| | - Martin Hale
- Department of Anatomical Pathology, National Health Laboratory Service, Johannesburg, South Africa
- Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Dana Holzinger
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Reza Malekzadeh
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Philip R Taylor
- Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, MD
| | - Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France
| | - Margaret I Urban
- National Health Laboratory Service, NHLS/MRC Cancer Epidemiology Research Group, Johannesburg, South Africa
- Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Freddy Sitas
- Cancer Council NSW, Cancer Research Division, Sydney, New South Wales, Australia
- School of Public Health, University of Sydney, New South Wales, Australia
- School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia
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