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Gusakov K, Kalinkovich A, Ashkenazi S, Livshits G. Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications. Nutrients 2024; 16:2569. [PMID: 39125448 PMCID: PMC11314534 DOI: 10.3390/nu16152569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients.
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Affiliation(s)
- Kirill Gusakov
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
| | - Alexander Kalinkovich
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel;
| | - Shai Ashkenazi
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
| | - Gregory Livshits
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel;
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Nikmanesh N, Hosseini S, Mirbagheri F, Asadsangabi K, Fattahi MR, Safarpour AR, Abarghooee EF, Moravej A, Shamsdin SA, Akrami H, Saghi SA, Nikmanesh Y. Knowledge on Human Papillomavirus Infections, Cancer Biology, Immune Interactions, Vaccination Coverage and Common Treatments: A Comprehensive Review. Viral Immunol 2024; 37:221-239. [PMID: 38841885 DOI: 10.1089/vim.2023.0144] [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] [Indexed: 06/07/2024] Open
Abstract
Human papillomavirus (HPV) is a circular, double-stranded DNA virus and recognized as the most prevalent sexually transmitted infectious agent worldwide. The HPV life cycle encompasses three primary stages. First, the virus infiltrates the basal cells of the stratified epidermis. Second, there is a low-level expression of viral genes and preservation of the viral genome in the basal layer. Lastly, productive replication of HPV occurs in differentiated cells. An effective immune response, involving various immune cells, including innate immunity, keratinocytes, dendritic cells, and natural killer T cells, is instrumental in clearing HPV infection and thwarting the development of HPV-associated tumors. Vaccines have demonstrated their efficacy in preventing genital warts, high-grade precancerous lesions, and cancers in females. In males, the vaccines can also aid in preventing genital warts, anal precancerous lesions, and cancer. This comprehensive review aims to provide a thorough and detailed exploration of HPV infections, delving into its genetic characteristics, life cycle, pathogenesis, and the role of high-risk and low-risk HPV strains. In addition, this review seeks to elucidate the intricate immune interactions that govern HPV infections, spanning from innate immunity to adaptive immune responses, as well as examining the evasion mechanisms used by the virus. Furthermore, the article discusses the current landscape of HPV vaccines and common treatments, contributing to a holistic understanding of HPV and its associated diseases.
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Affiliation(s)
- Nika Nikmanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - SeyedehZahra Hosseini
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran
| | | | - Kimiya Asadsangabi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Reza Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Reza Safarpour
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ali Moravej
- Department of Laboratory Sciences, School of Allied Medical Sciences, Fasa University of Medical Science, Fasa, Iran
| | - Seyedeh Azra Shamsdin
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hassan Akrami
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Amirreza Saghi
- Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran
- Student Research Committee, Faculty of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Nikmanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Suleman M, Khan TA, Ejaz H, Maroof S, Alshammari A, Albekairi NA, Khan H, Waheed Y, Khan A, Wei DQ, Crovella S. Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus. Microb Pathog 2024; 189:106572. [PMID: 38354987 DOI: 10.1016/j.micpath.2024.106572] [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: 10/31/2023] [Revised: 12/23/2023] [Accepted: 02/11/2024] [Indexed: 02/16/2024]
Abstract
The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.
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Affiliation(s)
- Muhammad Suleman
- Laboratory of Animal Research Center (LARC), Qatar University, Doha, Qatar; Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan.
| | - Tariq Aziz Khan
- Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan.
| | - Hadiqa Ejaz
- King Edward Medical University, Lahore, Pakistan.
| | - Sabahat Maroof
- Sharif Medical and Dental Colllege, Lahore, Punjab, Pakistan
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh, 11451, Saudi Arabia.
| | - Norah A Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh, 11451, Saudi Arabia.
| | - Haji Khan
- Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan.
| | - Yasir Waheed
- Office of Research, Innovation, and Commercialization (ORIC), Shaheed Zulfiqar Ali Bhutto Medical University (SZABMU), Islamabad, 44000, Pakistan; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, 1401, Lebanon
| | - Abbas Khan
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; Sunway Microbiome Centre, School of Medical and Life Sciences, Sunway University, 47500, Sunway City, Malaysia.
| | - Dong-Qing Wei
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Sergio Crovella
- Laboratory of Animal Research Center (LARC), Qatar University, Doha, Qatar.
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Kobayashi O, Taguchi A, Nakajima T, Ikeda Y, Saito K, Kawana K. Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer. Taiwan J Obstet Gynecol 2024; 63:22-28. [PMID: 38216264 DOI: 10.1016/j.tjog.2023.10.002] [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: 10/17/2023] [Indexed: 01/14/2024] Open
Abstract
Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.
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Affiliation(s)
- Osamu Kobayashi
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Takahiro Nakajima
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Keisuke Saito
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan.
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Romero-Masters JC, Muehlbauer LK, Hayes M, Grace M, Shishkova E, Coon JJ, Munger K, Lambert PF. MmuPV1 E6 induces cell proliferation and other hallmarks of cancer. mBio 2023; 14:e0245823. [PMID: 37905801 PMCID: PMC10746199 DOI: 10.1128/mbio.02458-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 09/22/2023] [Indexed: 11/02/2023] Open
Abstract
IMPORTANCE The Mus musculus papillomavirus 1 (MmuPV1) E6 and E7 proteins are required for MmuPV1-induced disease. Our understanding of the activities of MmuPV1 E6 has been based on affinity purification/mass spectrometry studies where cellular interacting partners of MmuPV1 E6 were identified, and these studies revealed that MmuPV1 E6 can inhibit keratinocyte differentiation through multiple mechanisms. We report that MmuPV1 E6 encodes additional activities including the induction of proliferation, resistance to density-mediated growth arrest, and decreased dependence on exogenous growth factors. Proteomic and transcriptomic analyses provided evidence that MmuPV1 E6 increases the expression and steady state levels of a number of cellular proteins that promote cellular proliferation and other hallmarks of cancer. These results indicate that MmuPV1 E6 is a major driver of MmuPV1-induced pathogenesis.
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Affiliation(s)
- James C. Romero-Masters
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Laura K. Muehlbauer
- Departments of Chemistry and Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mitchell Hayes
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Miranda Grace
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Evgenia Shishkova
- Departments of Chemistry and Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Joshua J. Coon
- Departments of Chemistry and Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Morgridge Institute for Research, Madison, Wisconsin, USA
| | - Karl Munger
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Jain M, Yadav D, Jarouliya U, Chavda V, Yadav AK, Chaurasia B, Song M. Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis. Pathogens 2023; 12:1380. [PMID: 38133265 PMCID: PMC10745624 DOI: 10.3390/pathogens12121380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/08/2023] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and -18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. In addition, vaccination awareness programs and preventive strategies could help reduce the rate and incidence of HPV infection. In this review, we emphasize HPV infection and its role in cancer progression, molecular and immunopathogenesis, host immune response, immune evasion by HPV, vaccination, and preventive schemes battling HPV infection and HPV-related cancers.
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Affiliation(s)
- Meenu Jain
- Department of Microbiology, Viral Research and Diagnostic Laboratory, Gajra Raja Medical College, Gwalior 474009, Madhya Pradesh, India
| | - Dhananjay Yadav
- Department of Life Science, Yeungnam University, Gyeongsan 38541, Republic of Korea;
| | - Urmila Jarouliya
- SOS in Biochemistry, Jiwaji University, Gwalior 474011 Madhya Pradesh, India;
| | - Vishal Chavda
- Department of Pathology, Stanford School of Medicine, Stanford University Medical Center, Palo Alto, CA 94305, USA;
| | - Arun Kumar Yadav
- Department of Microbiology, Guru Gobind Singh Medical College and Hospital, Baba Farid University of Health Sciences, Faridkot 151203, Punjab, India;
| | - Bipin Chaurasia
- Department of Neurosurgery, Neurosurgery Clinic, Birgunj 44300, Nepal;
| | - Minseok Song
- Department of Life Science, Yeungnam University, Gyeongsan 38541, Republic of Korea;
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Kusakabe M, Taguchi A, Sone K, Mori M, Osuga Y. Carcinogenesis and management of human papillomavirus-associated cervical cancer. Int J Clin Oncol 2023:10.1007/s10147-023-02337-7. [PMID: 37294390 PMCID: PMC10390372 DOI: 10.1007/s10147-023-02337-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/01/2023] [Indexed: 06/10/2023]
Abstract
Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.
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Affiliation(s)
- Misako Kusakabe
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
- Laboratory of Human Single Cell Immunology, World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mayuyo Mori
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
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Nguyen HDT, Le TM, Lee E, Lee D, Choi Y, Cho J, Park NJY, Chong GO, Seo I, Han HS. Relationship between Human Papillomavirus Status and the Cervicovaginal Microbiome in Cervical Cancer. Microorganisms 2023; 11:1417. [PMID: 37374919 DOI: 10.3390/microorganisms11061417] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/05/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Uterine cervical cancer (CC) is a complex, multistep disease primarily linked to persistent infection with high-risk human papillomavirus (HR-HPV). However, it is widely acknowledged that HR-HPV infection alone cannot account for the formation and progression of CC. Emerging evidence suggests that the cervicovaginal microbiome (CVM) also plays a significant role in HPV-related CC. Certain bacteria, such as Fusobacterium spp., Porphyromonas, Prevotella, and Campylobacter, are currently being considered as potential microbiomarkers for HPV-positive CC. However, the composition of the CVM in CC is inconsistent; thus, further studies are needed. This review comprehensively discusses the complex interplay between HPV and the CVM in cervical carcinogenesis. It is postulated that the dynamic interaction between HPV and the CVM creates an imbalanced cervicovaginal microenvironment that triggers dysbiosis, enhances HPV persistence, and promotes cervical carcinogenesis. Moreover, this review aims to provide updated evidence on the potential role of bacteriotherapy, particularly probiotics, in the treatment of CC.
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Affiliation(s)
- Hong Duc Thi Nguyen
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Tan Minh Le
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Eunmi Lee
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Donghyeon Lee
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Yeseul Choi
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Junghwan Cho
- Clinical Omics Institute, Kyungpook National University, Daegu 41405, Republic of Korea
| | - Nora Jee-Young Park
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Clinical Omics Institute, Kyungpook National University, Daegu 41405, Republic of Korea
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Pathology, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea
| | - Gun Oh Chong
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Clinical Omics Institute, Kyungpook National University, Daegu 41405, Republic of Korea
- Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Obstetrics and Gynecology, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea
| | - Incheol Seo
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Hyung Soo Han
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 Four Program, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Clinical Omics Institute, Kyungpook National University, Daegu 41405, Republic of Korea
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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Gandhi S, Mohamad Razif MF, Othman S, Chakraborty S, Nor Rashid N. Evaluation of the proteomic landscape of HPV E7‑induced alterations in human keratinocytes reveal therapeutically relevant pathways for cervical cancer. Mol Med Rep 2023; 27:46. [PMID: 36633133 DOI: 10.3892/mmr.2023.12933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 10/18/2022] [Indexed: 01/10/2023] Open
Abstract
The lack of specific and accurate therapeutic targets poses a challenge in the treatment of cervical cancer (CC). Global proteomics has the potential to characterize the underlying and intricate molecular mechanisms that drive the identification of therapeutic candidates for CC in an unbiased manner. The present study assessed human papillomavirus (HPV)‑induced proteomic alterations to identify key cancer hallmark pathways and protein‑protein interaction (PPI) networks, which offered the opportunity to evaluate the possibility of using these for targeted therapy in CC. Comparative proteomic profiling of HPV‑transfected (HPV16/18 E7), HPV‑transformed (CaSki and HeLa) and normal human keratinocyte (HaCaT) cells was performed using the liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) technique. Both label‑free quantification and differential expression analysis were performed to assess differentially regulated proteins in HPV‑transformed and ‑transfected cells. The present study demonstrated that protein expression was upregulated in HPV‑transfected cells compared with in HPV‑transformed cells. This was probably due to the ectopic expression of E7 protein in the former cell type, in contrast to its constitutive expression in the latter cell type. Subsequent pathway visualization and network construction demonstrated that the upregulated proteins in HPV16/18 E7‑transfected cells were predominantly associated with a diverse array of cancer hallmarks, including the mTORC1 signaling pathway, MYC targets V1, hypoxia and glycolysis. Among the various proteins present in the cancer hallmark enrichment pathways, phosphoglycerate kinase 1 (PGK1) was present across all pathways. Therefore, PGK1 may be considered as a potential biomarker. PPI analysis demonstrated a direct interaction between p130 and polyubiquitin B, which may lead to the degradation of p130 via the ubiquitin‑proteasome proteolytic pathway. In summary, elucidation of the key signaling pathways in HPV16/18‑transfected and ‑transformed cells may aid in the design of novel therapeutic strategies for clinical application such as targeted therapy and immunotherapy against cervical cancer.
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Affiliation(s)
- Sivasangkary Gandhi
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Shatrah Othman
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Sajib Chakraborty
- Translational System Biology Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, People's Republic of Bangladesh
| | - Nurshamimi Nor Rashid
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
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Abstract
The human papillomavirus (HPV) E6 and E7 oncogenes are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how HPV16 E6 and E7 alter the cellular response to the proinflammatory cytokine IL-1β. Models of early stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1β treatment. Such overlap in cell responses supports that changes induced by HPV16 E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV16 E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1β-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells. IMPORTANCE Human papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by proinflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1β in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
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11
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Haręża DA, Wilczyński JR, Paradowska E. Human Papillomaviruses as Infectious Agents in Gynecological Cancers. Oncogenic Properties of Viral Proteins. Int J Mol Sci 2022; 23:1818. [PMID: 35163748 PMCID: PMC8836588 DOI: 10.3390/ijms23031818] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/29/2022] [Accepted: 02/03/2022] [Indexed: 01/25/2023] Open
Abstract
Human papillomaviruses (HPVs), which belong to the Papillomaviridae family, constitute a group of small nonenveloped double-stranded DNA viruses. HPV has a small genome that only encodes a few proteins, and it is also responsible for 5% of all human cancers, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV types may be classified as high- and low-risk genotypes (HR-HPVs and LR-HPVs, respectively) according to their oncogenic potential. HR-HPV 16 and 18 are the most common types worldwide and are the primary types that are responsible for most HPV-related cancers. The activity of the viral E6 and E7 oncoproteins, which interfere with critical cell cycle points such as suppressive tumor protein p53 (p53) and retinoblastoma protein (pRB), is the major contributor to HPV-induced neoplastic initiation and progression of carcinogenesis. In addition, the E5 protein might also play a significant role in tumorigenesis. The role of HPV in the pathogenesis of gynecological cancers is still not fully understood, which indicates a wide spectrum of potential research areas. This review focuses on HPV biology, the distribution of HPVs in gynecological cancers, the properties of viral oncoproteins, and the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Daria A. Haręża
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 93-232 Lodz, Poland;
- BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, 90-237 Lodz, Poland
| | - Jacek R. Wilczyński
- Department of Surgical and Oncological Gynecology, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 93-232 Lodz, Poland;
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12
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Albarnaz JD, Ren H, Torres AA, Shmeleva EV, Melo CA, Bannister AJ, Brember MP, Chung BYW, Smith GL. Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat Microbiol 2022; 7:154-168. [PMID: 34949827 PMCID: PMC7614822 DOI: 10.1038/s41564-021-01004-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 10/21/2021] [Indexed: 12/16/2022]
Abstract
Infection of mammalian cells with viruses activates NF-κB to induce the expression of cytokines and chemokines and initiate an antiviral response. Here, we show that a vaccinia virus protein mimics the transactivation domain of the p65 subunit of NF-κB to inhibit selectively the expression of NF-κB-regulated genes. Using co-immunoprecipitation assays, we found that the vaccinia virus protein F14 associates with NF-κB co-activator CREB-binding protein (CBP) and disrupts the interaction between p65 and CBP. This abrogates CBP-mediated acetylation of p65, after which it reduces promoter recruitment of the transcriptional regulator BRD4 and diminishes stimulation of NF-κB-regulated genes CXCL10 and CCL2. Recruitment of BRD4 to the promoters of NFKBIA and CXCL8 remains unaffected by either F14 or JQ1 (a competitive inhibitor of BRD4 bromodomains), indicating that BRD4 recruitment is acetylation-independent. Unlike other viral proteins that are general antagonists of NF-κB, F14 is a selective inhibitor of NF-κB-dependent gene expression. An in vivo model of infection demonstrated that F14 promotes virulence. Molecular mimicry of NF-κB may be conserved because other orthopoxviruses, including variola, monkeypox and cowpox viruses, encode orthologues of F14.
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Affiliation(s)
- Jonas D Albarnaz
- Department of Pathology, University of Cambridge, Cambridge, UK.
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
| | - Hongwei Ren
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, UK
| | - Alice A Torres
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Evgeniya V Shmeleva
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK
| | - Carlos A Melo
- The Gurdon Institute, University of Cambridge, Cambridge, UK
| | | | | | - Betty Y-W Chung
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Geoffrey L Smith
- Department of Pathology, University of Cambridge, Cambridge, UK.
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13
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Sikdar A, Gupta R, Boura E. Reviewing Antiviral Research Against Viruses Causing Human Diseases - A Structure Guided Approach. Curr Mol Pharmacol 2021; 15:306-337. [PMID: 34348638 DOI: 10.2174/1874467214666210804152836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 11/22/2022]
Abstract
The littlest of all the pathogens, viruses have continuously been the foremost strange microorganisms to consider. Viral Infections can cause extreme sicknesses as archived by the HIV/AIDS widespread or the later Ebola or Zika episodes. Apprehensive framework distortions are too regularly watched results of numerous viral contaminations. Besides, numerous infections are oncoviruses, which can trigger different sorts of cancer. Nearly every year a modern infection species rises debilitating the world populace with an annihilating episode. Subsequently, the need of creating antivirals to combat such rising infections. In any case, from the innovation of to begin with antiviral medicate Idoxuridine in 1962 to the revelation of Baloxavir marboxil (Xofluza) that was FDA-approved in 2018, the hone of creating antivirals has changed significantly. In this article, different auxiliary science strategies have been described that can be referral for therapeutics innovation.
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Affiliation(s)
- Arunima Sikdar
- Department of Hematology and Oncology, School of Medicine, The University of Tennessee Health Science Center, 920 Madison Ave, P.O.Box-38103, Memphis, Tennessee. United States
| | - Rupali Gupta
- Department of Neurology, Duke University Medical Center, Durham, North Carolina. United States
| | - Evzen Boura
- Department of Molecular Biology and Biochemistry, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 542/2, P.O. Box:16000, Prague. Czech Republic
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14
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Vats A, Trejo-Cerro O, Thomas M, Banks L. Human papillomavirus E6 and E7: What remains? Tumour Virus Res 2021; 11:200213. [PMID: 33716206 PMCID: PMC7972986 DOI: 10.1016/j.tvr.2021.200213] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Decades of research on the human papillomavirus oncogenes, E6 and E7, have given us huge amounts of data on their expression, functions and structures. We know much about the very many cellular proteins and pathways that they influence in one way or another. However, much of this information is quite discrete, referring to one activity examined under one condition. It is now time to join the dots to try to understand a larger picture: how, where and when do all these interactions occur... and why? Examining these questions will also show how many of the yet obscure cellular processes work together for cellular and tissue homeostasis in health and disease.
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Affiliation(s)
- Arushi Vats
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Oscar Trejo-Cerro
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Miranda Thomas
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy.
| | - Lawrence Banks
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
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15
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Sun Y, Wang Z, Qiu S, Wang R. Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma. Int J Biol Sci 2021; 17:1104-1118. [PMID: 33867833 PMCID: PMC8040311 DOI: 10.7150/ijbs.58077] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 9th most common malignant tumor in the world. Based on the etiology, HNSCC has two main subtypes: human papillomavirus (HPV) -related and HPV-unrelated. HPV-positive HNSCC is more sensitive to treatment with favorable survival. Due to the different biological behaviors, individual therapy is necessary and urgently required to deduce the therapeutic intensity of HPV-positive disease and look for a more effective and toxicity-acceptable regimen for HPV-negative disease. EGFR amplification and PI3K/AKT/mTOR pathway aberrant activation are quite common in HPV-positive HNSCC. Besides, HPV infection alters immune cell infiltrating in HNSCC and encompasses a diverse and heterogeneous landscape with more immune infiltration. On the other hand, the chance of HPV-negative cancers harboring mutation on the P53 gene is significantly higher than that of HPV-positive disease. This review focuses on the updated preclinical and clinical data of HPV-positive and HPV-negative HNSCC and discusses the therapeutic strategies of different HPV status in HNSCC.
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Affiliation(s)
- Yingming Sun
- Department of Radiation and Medical Oncology, Affiliated Sanming First Hospital of Fujian Medical University, Sanming 365001, P. R. China
| | - Zhe Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, P. R. China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Sufang Qiu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital; Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, P.R. China
| | - Ruoyu Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, P. R. China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
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16
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Scarth JA, Patterson MR, Morgan EL, Macdonald A. The human papillomavirus oncoproteins: a review of the host pathways targeted on the road to transformation. J Gen Virol 2021; 102:001540. [PMID: 33427604 PMCID: PMC8148304 DOI: 10.1099/jgv.0.001540] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022] Open
Abstract
Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis.
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Affiliation(s)
- James A. Scarth
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
| | - Molly R. Patterson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
| | - Ethan L. Morgan
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
- Present address: Tumour Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institute of Health, Bethesda, MD 20892, USA
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK
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17
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Keratinocyte transglutaminase 2 promotes CCR6 + γδT-cell recruitment by upregulating CCL20 in psoriatic inflammation. Cell Death Dis 2020; 11:301. [PMID: 32355189 PMCID: PMC7193648 DOI: 10.1038/s41419-020-2495-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/09/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Keratinocyte-derived cytokines and chemokines amplify psoriatic inflammation by recruiting IL-17-producing CCR6+ γδT-cells and neutrophils. The expression of these cytokines and chemokines mainly depends on NF-κB activity; however, the pathway that activates NF-κB in response to triggering factors is poorly defined. Here, we show that transglutaminase 2 (TG2), previously reported to elicit a TH17 response by increasing IL-6 expression in a mouse model of lung fibrosis, mediates the upregulation of cytokines and chemokines by activating NF-κB in imiquimod (IMQ)-treated keratinocytes. TG2-deficient mice exhibited reduced psoriatic inflammation in skin treated with IMQ but showed systemic immune responses similar to wild-type mice. Experiments in bone marrow (BM) chimeric mice revealed that TG2 is responsible for promoting psoriatic inflammation in non-BM-derived cells. In keratinocytes, IMQ treatment activated TG2, which in turn activated NF-κB signaling, leading to the upregulation of IL-6, CCL20, and CXCL8 and increased leukocyte migration, in vitro. Consequently, TG2-deficient mice showed markedly decreased CCR6+ γδT-cell and neutrophil infiltration in IMQ-treated skin. Moreover, TG2 levels were higher in psoriatic skin than in normal skin and correlated with IL-6, CXCL8, and CCL20 levels. Therefore, these results indicate that keratinocyte TG2 acts as a critical mediator in the amplification of psoriatic inflammation.
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18
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Ferreira AR, Ramalho AC, Marques M, Ribeiro D. The Interplay between Antiviral Signalling and Carcinogenesis in Human Papillomavirus Infections. Cancers (Basel) 2020; 12:cancers12030646. [PMID: 32164347 PMCID: PMC7139948 DOI: 10.3390/cancers12030646] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/20/2022] Open
Abstract
Human papillomaviruses (HPV) are the causative agents of the most common sexually transmitted infection worldwide. While infection is generally asymptomatic and can be cleared by the host immune system, when persistence occurs, HPV can become a risk factor for malignant transformation. Progression to cancer is actually an unintended consequence of the complex HPV life cycle. Different antiviral defence mechanisms recognize HPV early in infection, leading to the activation of the innate immune response. However, the virus has evolved several specific strategies to efficiently evade the antiviral immune signalling. Here, we review and discuss the interplay between HPV and the host cell innate immunity. We further highlight the evasion strategies developed by different HPV to escape this cellular response and focus on the correlation with HPV-induced persistence and tumorigenesis.
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Affiliation(s)
| | | | | | - Daniela Ribeiro
- Correspondence: ; Tel.: +351-234-247 014; Fax: +351-234-372-587
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19
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The Host-Microbe Interplay in Human Papillomavirus-Induced Carcinogenesis. Microorganisms 2019; 7:microorganisms7070199. [PMID: 31337018 PMCID: PMC6680694 DOI: 10.3390/microorganisms7070199] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Every year nearly half a million new cases of cervix cancer are diagnosed worldwide, making this malignancy the fourth commonest cancer in women. In 2018, more than 270,000 women died of cervix cancer globally with 85% of them being from developing countries. The majority of these cancers are caused by the infection with carcinogenic strains of human papillomavirus (HPV), which is also causally implicated in the development of other malignancies, including cancer of the anus, penis cancer and head and neck cancer. HPV is by far the most common sexually transmitted infection worldwide, however, most infected people do not develop cancer and do not even have a persistent infection. The development of highly effective HPV vaccines against most common high-risk HPV strains is a great medical achievement of the 21st century that could prevent up to 90% of cervix cancers. In this article, we review the current understanding of the balanced virus-host interaction that can lead to either virus elimination or the establishment of persistent infection and ultimately malignant transformation. We also highlight the influence of certain factors inherent to the host, including the immune status, genetic variants and the coexistence of other microbe infections and microbiome composition in the dynamic of HPV infection induced carcinogenesis.
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20
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Santiago-Téllez A, Castrillón-Rivera LE, Palma-Ramos A, Bello-López JM, Sainz-Espuñes T, Contreras-Paredes A, Luna-Herrera J, Castañeda-Sánchez JI. Keratinocyte infection by Actinomadura madurae triggers an inflammatory response. Trans R Soc Trop Med Hyg 2019; 113:392-398. [PMID: 30989203 DOI: 10.1093/trstmh/trz022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/07/2019] [Accepted: 03/13/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Actinomycetoma is a syndrome of the skin characterized by chronic inflammation and lesions with nodular grain-like structures. The most common aetiological agents are Nocardia brasiliensis and Actinomadura madurae. In response to infection with these organisms the body produces an inflammatory immune response in the skin. The aim of the present study was to determine the production of chemokines, pro-inflammatory cytokines, antimicrobial peptides and the expression of Toll-like receptors (TLRs) in keratinocytes infected by A. madurae. METHODS A cell line of HaCaT keratinocytes was infected with A. madurae at a multiplicity of infection of 20:1 for 2 h and the samples were collected from 2 to 72 h post-infection. Intracellular replication of the bacterium was evaluated by counting of colony-forming units, the TLR expression and antimicrobial peptide production were assayed by confocal microscopy and chemokine and pro-inflammatory cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS Early in the infection, A. madurae was able to achieve intracellular replication in keratinocytes, however, the cells eventually controlled the infection. In response to the infection, keratinocytes overexpressed TLR2 and TLR6, produced high concentrations of cytokines monocyte chemoattractant protein-1, interleukin 8, human β-defensin-1, human β-defensin-2 and LL37 and low levels of tumour necrosis factor α. CONCLUSIONS The human keratinocytes contribute to the inflammatory process in response to A. madurae infection by overexpressing TLRs and producing chemokines, pro-inflammatory cytokines and antimicrobial peptides.
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Affiliation(s)
- Alfonso Santiago-Téllez
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico.,Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico
| | - Laura Estela Castrillón-Rivera
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico
| | - Alejandro Palma-Ramos
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico
| | - Juan Manuel Bello-López
- Unidad de Investigación en Microbiología y Toxicología, Hospital Juárez de México, Av. Instituto Politécnico Nacional 5160, Magdalena de las Salinas, Gustavo A. Madero, Mexico city, Mexico
| | - Teresita Sainz-Espuñes
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico
| | - Adriana Contreras-Paredes
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Avenida San Fernando 22, Sección XVI, Tlalpan, Mexico city, Mexico
| | - Julieta Luna-Herrera
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala S/N, Santo Tomás, Miguel Hidalgo, Mexico city, Mexico
| | - Jorge Ismael Castañeda-Sánchez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso 1100, Villa Quietud, Coyoacán, Mexico city, Mexico
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21
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Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1-NFκB-IL-6 signalling axis. PLoS Pathog 2019; 15:e1007835. [PMID: 31226168 PMCID: PMC6608985 DOI: 10.1371/journal.ppat.1007835] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 07/03/2019] [Accepted: 05/13/2019] [Indexed: 12/12/2022] Open
Abstract
Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Although the fundamental link between HPV infection and oncogenesis is established, the specific mechanisms of virus-mediated transformation are not fully understood. We previously demonstrated that the HPV encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 in primary human keratinocytes; however, the molecular basis for STAT3 activation in cervical cancer remains unclear. Here, we show that STAT3 phosphorylation in HPV positive cervical cancer cells is mediated primarily via autocrine activation by the pro-inflammatory cytokine Interleukin 6 (IL-6). Antibody-mediated blockade of IL-6 signalling in HPV positive cells inhibits STAT3 phosphorylation, whereas both recombinant IL-6 and conditioned media from HPV positive cells leads to increased STAT3 phosphorylation within HPV negative cervical cancer cells. Interestingly, we demonstrate that activation of the transcription factor NFκB, involving the small GTPase Rac1, is required for IL-6 production and subsequent STAT3 activation. Our data provides new insights into the molecular re-wiring of cancer cells by HPV E6. We reveal that activation of an IL-6 signalling axis drives the autocrine and paracrine phosphorylation of STAT3 within HPV positive cervical cancers cells and that activation of this pathway is essential for cervical cancer cell proliferation and survival. Greater understanding of this pathway provides a potential opportunity for the use of existing clinically approved drugs for the treatment of HPV-mediated cervical cancer.
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22
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Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes. J Virol 2019; 93:JVI.01216-18. [PMID: 30381489 DOI: 10.1128/jvi.01216-18] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/15/2018] [Indexed: 12/14/2022] Open
Abstract
Epstein-Barr virus (EBV) is implicated in the pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC). EBV-associated cancers harbor a latent EBV infection characterized by a lack of viral replication and the expression of viral oncogenes. Cellular changes promoted by HPV are comparable to those shown to facilitate EBV latency, though whether HPV-positive cells support a latent EBV infection has not been demonstrated. Using a model of direct EBV infection into HPV16-immortalized tonsillar cells grown in organotypic raft culture, we showed robust EBV replication in HPV-negative rafts but little to no replication in HPV-immortalized rafts. The reduced EBV replication was independent of immortalization, as human telomerase-immortalized normal oral keratinocytes supported robust EBV replication. Furthermore, we observed reduced EBV lytic gene expression and increased expression of EBER1, a noncoding RNA highly expressed in latently infected cells, in the presence of HPV. The use of human foreskin keratinocyte rafts expressing the HPV16 E6 and/or E7 oncogene(s) (HPV E6 and E7 rafts) showed that E7 was sufficient to reduce EBV replication. EBV replication is dependent upon epithelial differentiation and the differentiation-dependent expression of the transcription factors KLF4 and PRDM1. While KLF4 and PRDM1 levels were unaltered, the expression levels of KLF4 transcriptional targets, including late differentiation markers, were reduced in HPV E6 and E7 rafts compared to their levels in parental rafts. However, the HPV E7-mediated block in EBV replication correlated with delayed expression of early differentiation markers. Overall, this study reveals an HPV16-mediated block in EBV replication, through E7, that may facilitate EBV latency and long-term persistence in the tumor context.IMPORTANCE Using a model examining the establishment of EBV infection in HPV-immortalized tissues, we showed an HPV-induced interruption of the normal EBV life cycle reminiscent of a latent EBV infection. Our data support the notion that a persistent EBV epithelial infection depends upon preexisting cellular alterations and suggest the ability of HPV to promote such changes. More importantly, these findings introduce a model for how EBV coinfection may influence HPV-positive (HPV-pos) OSCC pathogenesis. Latently EBV-infected epithelial cells, as well as other EBV-associated head-and-neck carcinomas, exhibit oncogenic phenotypes commonly seen in HPV-pos OSCC. Therefore, an HPV-induced shift in the EBV life cycle toward latency would not only facilitate EBV persistence but also provide additional viral oncogene expression, which can contribute to the rapid progression of HPV-pos OSCC. These findings provide a step toward defining a role for EBV as a cofactor in HPV-positive oropharyngeal tumors.
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23
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Wetherill LF, Wasson CW, Swinscoe G, Kealy D, Foster R, Griffin S, Macdonald A. Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5. Antiviral Res 2018; 158:113-121. [PMID: 30096339 PMCID: PMC6156294 DOI: 10.1016/j.antiviral.2018.08.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 07/27/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023]
Abstract
Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation.
Imino sugars inhibit the viroporin activity of the E5 oncoprotein. Imino sugars likely interact at E5 protomer interfaces within a channel to prevent oligomerisation. Imino sugars and adamantanes block mitogenic signalling mediated by E5 from a range of high-risk HPV types. Viroporin inhibitors reduce mitogenic signalling in differentiating primary keratinocytes containing high-risk HPV18.
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Affiliation(s)
- Laura F Wetherill
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, UK; School of Medicine, Faculty of Medicine & Health, University of Leeds, Wellcome Trust Brenner Building, St James' University Hospital, Beckett St., Leeds, LS9 7TF, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Christopher W Wasson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Gemma Swinscoe
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - David Kealy
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Richard Foster
- School of Chemistry, Faculty of Mathematics and Physical Sciences, University of Leeds, Leeds, LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Stephen Griffin
- School of Medicine, Faculty of Medicine & Health, University of Leeds, Wellcome Trust Brenner Building, St James' University Hospital, Beckett St., Leeds, LS9 7TF, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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24
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Nuovo GJ, de Andrade CV, Wells SI, Brusadelli M, Nicol AF. New biomarkers of human papillomavirus infection in acute cervical intraepithelial neoplasia. Ann Diagn Pathol 2018; 36:21-27. [PMID: 29966832 DOI: 10.1016/j.anndiagpath.2018.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 06/19/2018] [Indexed: 11/28/2022]
Abstract
Acute human papillomavirus (HPV) infection of the cervix (cervical intraepithelial neoplasia, CIN) is marked by high copy episomal viral DNA and L1/L2 capsid protein expression (productive infection) in the cells towards the surface that facilitate sexual viral transmission. Viral DNA is low copy and not associated with viral capsid protein expression in the less differentiated lower part of the CIN (nonproductive infection). The purpose of this study was to examine the host response in these two areas. Serial section and co-localization analyses demonstrated that in 29/33 (88%) of cases the NF-κB pathway was activated and localized to the suprabasal nonproductively infected cells in the CIN lesions. There was a concomitant increased expression of importin-β, exportin-5, Mcl1, p16, Ki67 and cFLIP in 32/33 (96%) of CIN lesions that likewise localized primarily to the nonproductively infected cells. Only Ki67 and exportin-5 were expressed, though much less so, in the adjacent, normal squamous epithelia. The viral proteins E1^E4 and L1 were localized to productively infected cells whereas E6/E7 protein/RNA was rarely present in early CIN. It is concluded that the host viral response to acute cervical HPV infection includes strong increased expression of proteins besides p16 and Ki67. These include importin-β, exportin-5, Mcl1, and cFLIP in cells with low copy and relatively quiescent viral DNA that, in turn, may serve as new biomarkers of this disease.
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Affiliation(s)
- Gerard J Nuovo
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States of America; Phylogeny Laboratory, Powell, OH, United States of America.
| | - Cecilia Vianna de Andrade
- National Institute of Health of Women, Children, and Adolescents, Fernandes Figueira - IFF-FIOCRUZ, Rio de Janeiro, Brazil
| | - Susanne I Wells
- Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, United States of America; University of Cincinnati, Cincinnati, OH, United States of America
| | - Marion Brusadelli
- Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, United States of America; University of Cincinnati, Cincinnati, OH, United States of America
| | - Alcina F Nicol
- National Institute of Infectious Diseases Evandro Chagas - INI-Fiocruz, Rio de Janeiro, Brazil
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25
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Yuan J, Ni G, Wang T, Mounsey K, Cavezza S, Pan X, Liu X. Genital warts treatment: Beyond imiquimod. Hum Vaccin Immunother 2018; 14:1815-1819. [PMID: 29505317 DOI: 10.1080/21645515.2018.1445947] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Genital warts are one of the most common sexually transmitted diseases worldwide. The disease is a result of infection with low-risk types of human papillomaviruses, mostly type 6 and 11. Current therapies for genital warts are mainly ablative, or alternatively topical application of imiquimod cream and sinecatechin (polyphenon E) ointment to the warts. However, low patient compliance and high recurrence rate are significant problems for the treatment of genital warts by imiquimod and ablative therapies. We summarise recent literature in this area and propose combining imiquimod with other therapies to increase the efficacy of imiquimod.
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Affiliation(s)
- Jianwei Yuan
- a Institute of Molecular Diagnosis and Target Therapy, First Affiliated Hospital , Guangdong Pharmaceutical University , Guangzhou , Guangdong , China
| | - Guoying Ni
- c Inflammation and Healing research cluster, Faculty of Science, Health , Education and Engineering, University of the Sunshine Coast , Maroochydore DC , Australia
| | - Tianfang Wang
- b Genecology Research Centre, Faculty of Science, Health, Education and Engineering , University of the Sunshine Coast , Maroochydore DC , Australia
| | - Kate Mounsey
- c Inflammation and Healing research cluster, Faculty of Science, Health , Education and Engineering, University of the Sunshine Coast , Maroochydore DC , Australia
| | - Shelley Cavezza
- c Inflammation and Healing research cluster, Faculty of Science, Health , Education and Engineering, University of the Sunshine Coast , Maroochydore DC , Australia
| | - Xuan Pan
- a Institute of Molecular Diagnosis and Target Therapy, First Affiliated Hospital , Guangdong Pharmaceutical University , Guangzhou , Guangdong , China
| | - Xiaosong Liu
- a Institute of Molecular Diagnosis and Target Therapy, First Affiliated Hospital , Guangdong Pharmaceutical University , Guangzhou , Guangdong , China.,c Inflammation and Healing research cluster, Faculty of Science, Health , Education and Engineering, University of the Sunshine Coast , Maroochydore DC , Australia
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26
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Morgan EL, Wasson CW, Hanson L, Kealy D, Pentland I, McGuire V, Scarpini C, Coleman N, Arthur JSC, Parish JL, Roberts S, Macdonald A. STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle. PLoS Pathog 2018; 14:e1006975. [PMID: 29630659 PMCID: PMC5908086 DOI: 10.1371/journal.ppat.1006975] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 04/19/2018] [Accepted: 03/15/2018] [Indexed: 02/06/2023] Open
Abstract
Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The transcription factor signal transducer and activator of transcription (STAT)-3 is important for cell cycle progression and cell survival in response to cytokines and growth factors. STAT3 requires phosphorylation on Ser727, in addition to phosphorylation on Tyr705 to be transcriptionally active. In this study, we show that STAT3 is essential for the HPV life cycle in undifferentiated and differentiated keratinocytes. Primary human keratinocytes containing high-risk HPV18 genomes display enhanced STAT3 phosphorylation compared to normal keratinocytes. Expression of the E6 oncoprotein is sufficient to induce the dual phosphorylation of STAT3 at Ser727 and Tyr705 by a mechanism requiring Janus kinases and members of the MAPK family. E6-mediated activation of STAT3 induces the transcription of STAT3 responsive genes including cyclin D1 and Bcl-xL. Silencing of STAT3 protein expression by siRNA or inhibition of STAT3 activation by small molecule inhibitors, or by expression of dominant negative STAT3 phosphorylation site mutants, results in blockade of cell cycle progression. Loss of active STAT3 impairs HPV gene expression and prevents episome maintenance in undifferentiated keratinocytes and upon differentiation, lack of active STAT3 abolishes virus genome amplification and late gene expression. Organotypic raft cultures of HPV18 containing keratinocytes expressing a phosphorylation site STAT3 mutant display a profound reduction in suprabasal hyperplasia, which correlates with a loss of cyclin B1 expression and increased differentiation. Finally, increased STAT3 expression and phosphorylation is observed in HPV positive cervical disease biopsies compared to control samples, highlighting a role for STAT3 activation in cervical carcinogenesis. In summary, our data provides evidence of a critical role for STAT3 in the HPV18 life cycle.
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Affiliation(s)
- Ethan L. Morgan
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
| | - Christopher W. Wasson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
| | - Lucy Hanson
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - David Kealy
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
| | - Ieisha Pentland
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Victoria McGuire
- Division of Cell Signalling and Immunology, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom
| | - Cinzia Scarpini
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Nicholas Coleman
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - J. Simon C. Arthur
- Division of Cell Signalling and Immunology, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom
| | - Joanna L. Parish
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Sally Roberts
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
- * E-mail:
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27
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Wittekindt C, Wagner S, Sharma SJ, Würdemann N, Knuth J, Reder H, Klußmann JP. [HPV - A different view on Head and Neck Cancer]. Laryngorhinootologie 2018; 97:S48-S113. [PMID: 29905354 PMCID: PMC6540966 DOI: 10.1055/s-0043-121596] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck cancer is the sixth most common cancer with over 500000 annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas (OSCC) show increased association with human papillomavirus (HPV). HPV-associated and HPV-negative OSCC are 2 different entities regarding biological characteristics, therapeutic response, and patient prognosis. In HPV OSCC, viral oncoprotein activity, as well as genetic (mutations and chromosomal aberrations) and epigenetic alterations plays a key role during carcinogenesis. Based on improved treatment response, the introduction of therapy de-intensification and targeted therapy is discussed for patients with HPV OSCC. A promising targeted therapy concept is immunotherapy. The use of checkpoint inhibitors (e.g. anti-PD1) is currently investigated. By means of liquid biopsies, biomarkers such as viral DNA or tumor mutations in the will soon be available for disease monitoring, as well as detection of treatment failure. By now, primary prophylaxis of HPV OSCC can be achieved by vaccination of girls and boys.
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Affiliation(s)
- Claus Wittekindt
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Steffen Wagner
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Shachi Jenny Sharma
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Nora Würdemann
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Jennifer Knuth
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Henrike Reder
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Jens Peter Klußmann
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
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28
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Bashaw AA, Leggatt GR, Chandra J, Tuong ZK, Frazer IH. Modulation of antigen presenting cell functions during chronic HPV infection. PAPILLOMAVIRUS RESEARCH (AMSTERDAM, NETHERLANDS) 2017; 4:58-65. [PMID: 29179871 PMCID: PMC5883240 DOI: 10.1016/j.pvr.2017.08.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/14/2017] [Accepted: 08/15/2017] [Indexed: 12/12/2022]
Abstract
High-risk human papillomaviruses (HR-HPV) infect basal keratinocytes, where in some individuals they evade host immune responses and persist. Persistent HR-HPV infection of the cervix causes precancerous neoplasia that can eventuate in cervical cancer. Dendritic cells (DCs) are efficient in priming/cross-priming antigen-specific T cells and generating antiviral and antitumor cytotoxic CD8+ T cells. However, HR-HPV have adopted various immunosuppressive strategies, with modulation of DC function crucial to escape from the host adaptive immune response. HPV E6 and E7 oncoproteins alter recruitment and localization of epidermal DCs, while soluble regulatory factors derived from HPV-induced hyperplastic epithelium change DC development and influence initiation of specific cellular immune responses. This review focuses on current evidence for HR-HPV manipulation of antigen presentation in dendritic cells and escape from host immunity.
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Affiliation(s)
- Abate Assefa Bashaw
- The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, Queensland 4102, Australia
| | - Graham R Leggatt
- The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, Queensland 4102, Australia
| | - Janin Chandra
- The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, Queensland 4102, Australia
| | - Zewen K Tuong
- The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, Queensland 4102, Australia
| | - Ian H Frazer
- The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, Queensland 4102, Australia.
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29
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RNA-Seq Analysis of Differentiated Keratinocytes Reveals a Massive Response to Late Events during Human Papillomavirus 16 Infection, Including Loss of Epithelial Barrier Function. J Virol 2017; 91:JVI.01001-17. [PMID: 29021401 PMCID: PMC5709591 DOI: 10.1128/jvi.01001-17] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 09/18/2017] [Indexed: 01/06/2023] Open
Abstract
The human papillomavirus (HPV) replication cycle is tightly linked to epithelial cell differentiation. To examine HPV-associated changes in the keratinocyte transcriptome, RNAs isolated from undifferentiated and differentiated cell populations of normal, spontaneously immortalized keratinocytes (NIKS) and NIKS stably transfected with HPV16 episomal genomes (NIKS16) were compared using next-generation sequencing (RNA-Seq). HPV16 infection altered expression of 2,862 cellular genes. Next, to elucidate the role of keratinocyte gene expression in late events during the viral life cycle, RNA-Seq was carried out on triplicate differentiated populations of NIKS (uninfected) and NIKS16 (infected). Of the top 966 genes altered (>log2 = 1.8, 3.5-fold change), 670 genes were downregulated and 296 genes were upregulated. HPV downregulated many genes involved in epithelial barrier function, which involves structural resistance to the environment and immunity to infectious agents. For example, HPV infection repressed expression of the differentiated keratinocyte-specific pattern recognition receptor TLR7, the Langerhans cell chemoattractant CCL20, and proinflammatory cytokines interleukin 1α (IL-1α) and IL-1β. However, the type I interferon regulator IRF1, kappa interferon (IFN-κ), and viral restriction factors (IFIT1, -2, -3, and -5, OASL, CD74, and RTP4) were upregulated. HPV infection abrogated gene expression associated with the physical epithelial barrier, including keratinocyte cytoskeleton, intercellular junctions, and cell adhesion. Quantitative PCR (qRT-PCR) and Western blotting confirmed changes in expression of seven of the most significantly altered mRNAs. Expression of three genes showed statistically significant changes during cervical disease progression in clinical samples. Taken together, the data indicate that HPV infection manipulates the differentiating keratinocyte transcriptome to create an environment conducive to productive viral replication and egress. IMPORTANCE HPV genome amplification and capsid formation take place in differentiated keratinocytes. The viral life cycle is intimately associated with host cell differentiation. Deep sequencing (RNA-Seq) of RNA from undifferentiated and differentiated uninfected and HPV16-positive keratinocytes showed that almost 3,000 genes were differentially expressed in keratinocytes due to HPV16 infection. Strikingly, the epithelial barrier function of differentiated keratinocytes, comprising keratinocyte immune function and cellular structure, was found to be disrupted. These data provide new insights into the virus-host interaction that is crucial for the production of infectious virus and reveal that HPV infection remodels keratinocytes for completion of the virus replication cycle.
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30
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Westrich JA, Warren CJ, Pyeon D. Evasion of host immune defenses by human papillomavirus. Virus Res 2017; 231:21-33. [PMID: 27890631 PMCID: PMC5325784 DOI: 10.1016/j.virusres.2016.11.023] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 11/10/2016] [Accepted: 11/12/2016] [Indexed: 12/13/2022]
Abstract
A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses.
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Affiliation(s)
- Joseph A Westrich
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Cody J Warren
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Current address: BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Dohun Pyeon
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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31
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Songock WK, Kim SM, Bodily JM. The human papillomavirus E7 oncoprotein as a regulator of transcription. Virus Res 2016; 231:56-75. [PMID: 27818212 DOI: 10.1016/j.virusres.2016.10.017] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 10/27/2016] [Indexed: 12/12/2022]
Abstract
High-risk human papillomaviruses (HPVs) encode oncoproteins which manipulate gene expression patterns in the host keratinocytes to facilitate viral replication, regulate viral transcription, and promote immune evasion and persistence. In some cases, oncoprotein-induced changes in host cell behavior can cause progression to cancer, but a complete picture of the functions of the viral oncoproteins in the productive HPV life cycle remains elusive. E7 is the HPV-encoded factor most responsible for maintaining cell cycle competence in differentiating keratinocytes. Through interactions with dozens of host factors, E7 has an enormous impact on host gene expression patterns. In this review, we will examine the role of E7 specifically as a regulator of transcription. We will discuss mechanisms of regulation of cell cycle-related genes by E7 as well as genes involved in immune regulation, growth factor signaling, DNA damage responses, microRNAs, and others pathways. We will also discuss some unanswered questions about how transcriptional regulation by E7 impacts the biology of HPV in both benign and malignant conditions.
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Affiliation(s)
- William K Songock
- Department of Microbiology and Immunology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Seong-Man Kim
- Department of Microbiology and Immunology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Jason M Bodily
- Department of Microbiology and Immunology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
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32
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Manipulation of the innate immune response by human papillomaviruses. Virus Res 2016; 231:34-40. [PMID: 27826042 DOI: 10.1016/j.virusres.2016.11.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 10/27/2016] [Accepted: 11/03/2016] [Indexed: 11/20/2022]
Abstract
The innate immune response constitutes the first line of defense against infections by pathogens. Successful pathogens such as human papillomaviruses (HPVs) have evolved mechanisms that target several points in these pathways including sensing of viral genomes, blocking the synthesis of interferons and inhibiting the action of JAK/STAT transcription factors. Disruption of these inhibitory mechanisms contributes to the ability of HPVs to establish persistent infections, which is the major etiological factor in the development of anogenital cancers. Interestingly, HPVs also positively activate several members of these pathways such as STAT-5 that are important for their differentiation-dependent life cycle. STAT-5 activation induces the ATM and ATR DNA damage response pathways that play critical roles in HPV genome amplification. Targeting of these pathways by pharmaceuticals can provide novel opportunities to inhibit infections by these important human pathogens.
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