|
1
|
Pan F, van der Schans J, Nazrul N, Koot JAR, Beltman J, Greuter MJW, de Bock GH. The effect of hrHPV prevalence on cervical cancer screening strategies: a cost-effectiveness study of Bangladesh. BMC Public Health 2025; 25:561. [PMID: 39934769 DOI: 10.1186/s12889-025-21756-x] [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: 11/12/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Cervical cancer is the second most prominent cancer among women in Bangladesh, which is mainly caused by persistent infection with high-risk human papillomavirus (hrHPV). This study aims to evaluate impact of hrHPV prevalence on cost-effectiveness of screening with self-sampling hrHPV testing versus visual inspection with acetic acid (VIA) for cervical cancer screening in low- and middle-income countries with Bangladesh as an example. METHODS A micro-simulation Markov model was developed from a health system perspective in Bangladesh to evaluate the cost-effectiveness of screening with self-sampling hrHPV testing followed by VIA and VIA as primary screening method followed by colposcopy. We compared these strategies in optimal (70%) and realistic (8.7%) uptake scenarios, considering different hrHPV prevalence rates. Key indicators for cost-effectiveness were number of prevented cervical cancers cases and incremental cost-effectiveness ratio (ICER). RESULTS The number of cervical cancers cases prevented by screening and cost-effectiveness of screening strategies increased as hrHPV prevalence increased. In both optimal and realistic uptake scenarios, hrHPV test + VIA strategy prevented more cancers than VIA + colposcopy strategy in most instances. Regardless of the uptake, both screening strategies were cost-effective compared to no screening within a hrHPV prevalence range of 2-30%, and the hrHPV test-based strategy was cost-effective compared with VIA-based strategy. When the price of hrHPV test was estimated 50% lower (10 USD), the hrHPV test-based strategy gained more life years at nearly the same cost as the VIA-based strategy. CONCLUSIONS Our study demonstrates that the hrHPV test + VIA strategy is cost-effective both compared to no screening and VIA + colposcopy screening strategy under the optimal (70%) and realistic (8.7%) uptake scenarios, with greater cost-effectiveness at higher hrHPV prevalence levels. While VIA-based strategy is cheaper, self-sampling hrHPV test-based strategy offers greater health benefits. Implementing hrHPV testing in national screening programs at lower hrHPV test prices is crucial for promoting health equity and accelerating cervical cancer elimination worldwide. In resource-constrained settings, screening with hrHPV testing should initially target high-prevalence populations.
Collapse
Affiliation(s)
- Fengming Pan
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Jurjen van der Schans
- Unit of Global Health, Department of Health Sciences, University Medical Center Groningen, Groningen, The Netherlands
- Department of Economics, Econometrics & Finance, University of Groningen, Groningen, The Netherlands
- Faculty of Management Sciences, Open University, Heerlen, The Netherlands
| | | | - Jaap A R Koot
- Unit of Global Health, Department of Health Sciences, University Medical Center Groningen, Groningen, The Netherlands
| | - Jogchum Beltman
- Department of Gynecology, Leiden University Medical Centre, Leiden University, Leiden, The Netherlands
| | - Marcel J W Greuter
- Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Geertruida H de Bock
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| |
Collapse
|
|
2
|
Kalra P, Ali S, Ocen S. Modelling on COVID-19 control with double and booster-dose vaccination. Gene 2024; 928:148795. [PMID: 39097207 DOI: 10.1016/j.gene.2024.148795] [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: 02/29/2024] [Revised: 06/03/2024] [Accepted: 07/22/2024] [Indexed: 08/05/2024]
Abstract
COVID-19 vaccines have been illustrated to lessen the growth of sickness caused by the virus effectively. In any case, inoculation has consistently been controversial, with differing opinions and viewpoints. This has compelled some individuals to decide against receiving the vaccine. These divergent viewpoints have had a trivial impact on the epidemic's dynamics and the disease's development. In response to vaccinated individuals still falling ill, many countries have implemented booster vaccines to protect further. In this specific investigation, a mathematical model composed of seven compartments is employed to examine the effectiveness of a booster dose in preventing and treating the transmission of COVID-19. The principles of mathematics are employed to analyse and investigate the dynamics of the disease. Using a qualitative prototype analysis, we acquired valuable insights into its effectiveness. One essential aspect is the basic reproduction number, a critical determinant of the disease's spread. This calculation is determined by studying the system's equilibrium and evaluating its stability. Furthermore, we examined the balance from a local and global viewpoint, considering the possibility of bifurcation and the model's reproductive number sensitivity index. Through numerical simulations, we have visually illustrated the analytical findings outlined in this research paper and presented a thorough examination of the efficacy of booster shots as a preventive and therapeutic measure in the spread dynamics of COVID-19.
Collapse
Affiliation(s)
- Preety Kalra
- Department of Mathematics, School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara 144411, India.
| | - Shoket Ali
- Department of Mathematics, School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara 144411, India
| | - Samuel Ocen
- Department of Mathematics, School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara 144411, India
| |
Collapse
|
|
3
|
Tao H, Yu F, Yang L, Pei X, Mao S, Fan X. Comparing the performance of DeoxyriboNucleic Acid methylation analysis and cytology for detecting cervical (pre)cancer in women with high-risk human papillomavirus-positive status in a gynecologic outpatient population. BMC Cancer 2024; 24:1352. [PMID: 39497123 PMCID: PMC11536530 DOI: 10.1186/s12885-024-13126-4] [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: 09/25/2024] [Accepted: 10/29/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Primary screening for high-risk human papillomavirus (hrHPV) with cytological triage for women with non-16/18 hrHPV-positive status has become popular in China. However, cytology relies on the subjective judgment of pathologists, leading to inconsistent clinical performance. METHODS A total of 657 hrHPV-positive women aged 25-64 years were enrolled in this cross-sectional study. All participants underwent colposcopic biopsy after cytology triage, with cytology residual specimens undergoing DNA methylation testing. CIN2+ and CIN3+ sensitivity and specificity were compared between the different triage strategies (n=487): PAX1 methylation (PAX1m) , Glycophorin C methylation (GYPCm), cytology, and combinations between them or with HPV16/18. RESULTS The area under the receiver operating characteristic curves (AUCs) for PAX1m and GYPCm in detecting CIN2 or worse (CIN2+) were 0.867 (95% confidence interval [CI]: 0.796-0.937) and 0.873 (95% CI: 0.808-0.938), respectively. The sensitivities of PAX1m and GYPCm were consistent with those of cytology for both CIN2+ and CIN3+ detection. The relative specificities of PAX1m and GYPCm for CIN2+ detection compared to cytology were 2.83 (95% CI: 2.33-2.45) and 3.09 (95% CI: 2.40-3.98), respectively. The relative specificities of combining HPV 16/18 with PAX1m and GYPCm for CIN2+ detection compared to cytology were 3.38 (95% CI: 2.96-3.86) and 3.67 (95% CI: 3.15-4.27), respectively. Compared to low levels of DNA methylation, high levels of PAX1m and GYPCm resulted in odd ratios (ORs) of 57.66 (95% CI: 13.57-409.12, p < 0.001) and 23.87 (95% CI: 6.49-115.42, p < 0.001) for CIN3+, adjusted for HPV 16/18 and cytology results. CONCLUSIONS PAX1m and GYPCm demonstrated superior ability to identify cervical precancerous lesions and cervical cancer, with AUC values exceeding 0.85. For detecting CIN2+/CIN3+ in women with hrHPV-positive status, DNA methylation (combined with HPV 16/18) showed higher specificity than cytology (combined with HPV 16/18) and is a potential molecular biomarker for detecting cervical (pre)cancer.
Collapse
Affiliation(s)
- Hong Tao
- Department of Medical Statistics, Hunan Hoomya Gene Technology Co., Ltd, Changsha, 410205, China
| | - Fang Yu
- Department of Obstetrics & Gynecology, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Li Yang
- Department of Obstetrics & Gynecology, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Xiaozhu Pei
- Department of Medical Statistics, Hunan Hoomya Gene Technology Co., Ltd, Changsha, 410205, China
| | - Saiping Mao
- Department of Obstetrics & Gynecology, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Xing Fan
- Department of Obstetrics & Gynecology, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China.
| |
Collapse
|
|
4
|
Tian Y, Zhang S, Ni F. Targeting glucose metabolism for HPV-associated cervical cancer: A sweet poison. Biomed Pharmacother 2024; 180:117519. [PMID: 39378679 DOI: 10.1016/j.biopha.2024.117519] [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: 08/05/2024] [Revised: 09/28/2024] [Accepted: 10/04/2024] [Indexed: 10/10/2024] Open
Abstract
More than 99 % of precancerous cervical lesions are associated with human papillomavirus (HPV) infection, with HPV types 16 and 18 (especially type 16) found in over 70 % of cervical cancer cases globally. The growth of HPV-positive cervical cancer depends on the sustained expression of the viral oncogenes E6 and E7, which are key factors in maintaining the malignant phenotype of HPV-positive tumor cells. E6 and E7 oncoproteins can cause the degradation of the tumor suppressor gene p53 and the inactivation of pRb, respectively, thereby inducing carcinogenesis. However, the inhibition of p53 and pRb cannot fully explain the oncogenic mechanism of cervical cancer. Although the development of the HPV vaccine has controlled the incidence of HPV infection, its application and widespread adoption remain limited. In addition, many developing countries cannot afford the cost of vaccines. More importantly, the vaccine only prevents HPV infection and does not provide an effective treatment for patients who are already infected or have cervical cancer. Therefore, HPV-related diseases, especially cervical cancer, remain a serious challenge. This article reviews the role of glucose metabolism changes and key molecular events in HPV-induced cervical cancer, summarizes potential targets for the treatment of cervical cancer, and provides strategies for future clinical treatment. It also offers a theoretical basis for research into cervical cancer and other HPV-related tumors. Furthermore, we discuss potential treatments for HPV-associated cervical cancer through targeted metabolic pathways and analyze the risks and challenges of current targeted glucose metabolism therapies for cervical cancer.
Collapse
Affiliation(s)
- Yuan Tian
- Department of Anesthesiology, Shenzhen Longhua District Central Hospital, China.
| | - Songyang Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Fushun Ni
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| |
Collapse
|
|
5
|
Sultanov M, Koot JAR, de Bock GH, Greuter MJW, Beltman JJ, de Fouw M, de Zeeuw J, Kabukye J, Stekelenburg J, van der Schans J. High-risk human papillomavirus testing for cervical cancer screening in Uganda: Considering potential harms and benefits in a low-resource setting. PLoS One 2024; 19:e0312295. [PMID: 39441790 PMCID: PMC11498676 DOI: 10.1371/journal.pone.0312295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
OBJECTIVES The World Health Organization supports both the screen-and-treat (ST) approach and the screen, triage and treat (STT) approach to cervical cancer screening using high-risk human papillomavirus (hrHPV) testing. For Uganda, the sequence of hrHPV-ST and hrHPV-STT could be similar, with visual inspection with acetic acid (VIA) after positive hrHPV tests in both. To consider potential tradeoffs (overtreatment in ST versus missed cancer cases in STT), we compared hrHPV-STT with VIA triage (STT-VIA), and STT with HPV 16/18 genotyping risk stratification, to hrHPV-ST for Uganda, in terms of overtreatment, cervical cancer incidence, and life years, for the general female population of Uganda. METHODS A microsimulation model of cervical cancer was adapted. Incremental benefit-harm ratios of STT were calculated as ratios of prevented overtreatment to reduced life years, and to increased cancer cases. Additional scenarios with 20% difference in intra- and inter-screening follow-up between ST and STT were modeled. RESULTS Both STT strategies resulted in life year losses on average compared to ST. STT-VIA prevented more overtreatment but led to increased cervical cancer incidence and life year losses. STT-G-VIA resulted in better harm-benefit ratios and additional costs. With better follow-up, STT prevented overtreatment and improved outcomes. DISCUSSION For Uganda, the STT approach appears preferrable, if the screening sequences of hrHPV-based ST and STT are similar in practice. While VIA triage alone would reduce overtreatment the most, it could also result in more cancer cases. Risk stratification via genotyping could improve STT. Potential follow-up differences and resource availability should be considered by decision-makers when planning Uganda's hrHPV-based screening strategy.
Collapse
Affiliation(s)
- Marat Sultanov
- Global Health Unit, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jaap A. R. Koot
- Global Health Unit, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Geertruida H. de Bock
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Marcel J. W. Greuter
- Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jogchum J. Beltman
- Department of Gynecology, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Marlieke de Fouw
- Department of Gynecology, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Janine de Zeeuw
- Global Health Unit, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | | | - Jelle Stekelenburg
- Global Health Unit, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Obstetrics and Gynecology, Medical Center Leeuwarden, Leeuwarden, Netherlands
| | - Jurjen van der Schans
- Global Health Unit, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Department of Economics, Econometrics and Finance, Faculty of Economics and Business, University of Groningen, Groningen, Netherlands
| |
Collapse
|
|
6
|
Luo H, Lian Y, Tao H, Zhao Y, Wang Z, Zhou J, Zhang Z, Jiang S. Relationship between p16/ki67 immunoscores and PAX1/ZNF582 methylation status in precancerous and cancerous cervical lesions in high-risk HPV-positive women. BMC Cancer 2024; 24:1171. [PMID: 39304838 PMCID: PMC11414254 DOI: 10.1186/s12885-024-12920-4] [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: 04/29/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND The risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0-3 each)-p16/Ki67 collectively known as an immunoscore [IS]-are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation. METHODS In this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed. RESULTS The ΔCp of PAX1m (PAX1 methylation) and ZNF582m (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1m/ZNF582m increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5-6, and the PAX1m/ZNF582m was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3-4 and were PAX1m/ZNF582m-positive in ≤ CIN1; 1 case had an IS of 0-2 and was PAX1m/ZNF582m-positive in CIN2/3. CONCLUSIONS Significant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3.
Collapse
Affiliation(s)
- Haijun Luo
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Yixiang Lian
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Hong Tao
- Department of Medical Statistics, Hunan Hoomya Gene Technology Co., Ltd., Changsha, 410205, China
| | - Yan Zhao
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Zhigan Wang
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Jing Zhou
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Zirong Zhang
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Shali Jiang
- Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China.
| |
Collapse
|
|
7
|
Molina MA, Steenbergen RDM, Pumpe A, Kenyon AN, Melchers WJG. HPV integration and cervical cancer: a failed evolutionary viral trait. Trends Mol Med 2024; 30:890-902. [PMID: 38853085 DOI: 10.1016/j.molmed.2024.05.009] [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: 03/08/2024] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/11/2024]
Abstract
Countless efforts have been made to eradicate cervical cancer worldwide, including improving disease screening and human papillomavirus (HPV) vaccination programs. Nevertheless, cervical cancer still claims the lives of more than 300 000 women every year. Persistent infections with high-risk HPV genotypes 16 and 18 are the main cause of cancer and may result in HPV integration into the host genome. The central dogma is that HPV integration is an important step in oncogenesis, but in fact, it impedes the virus from replicating and spreading. HPV causing cervical cancer can therefore be perceived as a failed evolutionary viral trait. Here we outline the occurrence and mechanisms of HPV integration and how this process results in oncogenic transformation.
Collapse
Affiliation(s)
- Mariano A Molina
- Department of Pathology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Cancer Centre Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
| | - Renske D M Steenbergen
- Department of Pathology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Cancer Centre Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands
| | - Anna Pumpe
- Department of Medical Microbiology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands
| | - Angelique N Kenyon
- Department of Medical Microbiology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands
| | - Willem J G Melchers
- Department of Medical Microbiology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands
| |
Collapse
|
|
8
|
Kawase K, Taguchi A, Ishizaka A, Lin J, Ueno T, Yoshimoto D, Eguchi S, Mori S, Sone K, Mori M, Yonekura S, Hanazawa T, Maeda D, Kukimoto I, Mano H, Osuga Y, Kawana K, Kawazu M. Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia. HLA 2024; 103:e15509. [PMID: 38837741 DOI: 10.1111/tan.15509] [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: 01/29/2024] [Revised: 03/28/2024] [Accepted: 04/18/2024] [Indexed: 06/07/2024]
Abstract
Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen-presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen-presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen-presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA-B alleles had a higher HPV antigen-presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2-3) than in cervicitis or early-stage CIN (CIN1): around half of CIN2-3 had LOH of any HLA class I. Moreover, the antigen-presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA-B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long-term infection and progression to advanced lesions.
Collapse
Affiliation(s)
- Katsushige Kawase
- Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
- Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Aya Ishizaka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jason Lin
- Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Toshihide Ueno
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Daisuke Yoshimoto
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoko Eguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seiichiro Mori
- Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mayuyo Mori
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Syuji Yonekura
- Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Daichi Maeda
- Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Iwao Kukimoto
- Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan
| | - Masahito Kawazu
- Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| |
Collapse
|
|
9
|
Garg P, Krishna M, Subbalakshmi AR, Ramisetty S, Mohanty A, Kulkarni P, Horne D, Salgia R, Singhal SS. Emerging biomarkers and molecular targets for precision medicine in cervical cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189106. [PMID: 38701936 DOI: 10.1016/j.bbcan.2024.189106] [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: 03/04/2024] [Revised: 04/18/2024] [Accepted: 04/28/2024] [Indexed: 05/06/2024]
Abstract
Cervical cancer remains a significant global health burden, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Precision medicine has emerged as a promising paradigm, leveraging biomarkers and molecular targets to tailor therapy to individual patients. This review explores the landscape of emerging biomarkers and molecular targets in cervical cancer, highlighting their potential implications for precision medicine. By integrating these biomarkers into comprehensive diagnostic algorithms, clinicians can identify high-risk patients at an earlier stage, enabling timely intervention and improved patient outcomes. Furthermore, the identification of specific molecular targets has paved the way for the development of targeted therapies aimed at disrupting key pathways implicated in cervical carcinogenesis. In conclusion, the evolving landscape of biomarkers and molecular targets presents exciting opportunities for advancing precision medicine in cervical cancer. By harnessing these insights, clinicians can optimize treatment selection, enhance patient outcomes, and ultimately transform the management of this devastating disease.
Collapse
Affiliation(s)
- Pankaj Garg
- Department of Chemistry, GLA University, Mathura, Uttar Pradesh 281406, India
| | - Madhu Krishna
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Ayalur Raghu Subbalakshmi
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sravani Ramisetty
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Atish Mohanty
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Prakash Kulkarni
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Departments of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Ravi Salgia
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Departments of Medical Oncology & Therapeutics Research and Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
| |
Collapse
|
|
10
|
Mallick S, Choi Y, Taylor AM, Cosper PF. Human Papillomavirus-Induced Chromosomal Instability and Aneuploidy in Squamous Cell Cancers. Viruses 2024; 16:501. [PMID: 38675844 PMCID: PMC11053578 DOI: 10.3390/v16040501] [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: 02/04/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. CIN is defined as a continuous rate of chromosome missegregation events over the course of multiple cell divisions. CIN causes aneuploidy, a state of abnormal chromosome content differing from a multiple of the haploid. Human papillomavirus (HPV) is a well-known cause of squamous cancers of the oropharynx, cervix, and anus. The HPV E6 and E7 oncogenes have well-known roles in carcinogenesis, but additional genomic events, such as CIN and aneuploidy, are often required for tumor formation. HPV+ squamous cancers have an increased frequency of specific types of CIN, including polar chromosomes. CIN leads to chromosome gains and losses (aneuploidies) specific to HPV+ cancers, which are distinct from HPV- cancers. HPV-specific CIN and aneuploidy may have implications for prognosis and therapeutic response and may provide insight into novel therapeutic vulnerabilities. Here, we review HPV-specific types of CIN and patterns of aneuploidy in squamous cancers, as well as how this impacts patient prognosis and treatment.
Collapse
Affiliation(s)
- Samyukta Mallick
- Department of Pathology and Cell Biology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY 10032, USA
| | - Yeseo Choi
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Cancer Biology Graduate Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Alison M. Taylor
- Department of Pathology and Cell Biology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Pippa F. Cosper
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA
| |
Collapse
|
|
11
|
Dutta P, Pal D, Roy A, Mandal RK, Panda CK. Role of MLH1 and MSH2 deficiency in the development of tumorigenesis and chemo-tolerance of cervical Carcinoma: Clinical implications. Gene 2023; 888:147746. [PMID: 37657688 DOI: 10.1016/j.gene.2023.147746] [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: 06/26/2023] [Revised: 07/27/2023] [Accepted: 08/28/2023] [Indexed: 09/03/2023]
Abstract
Cervical cancer (CACX) is one of the top causes of cancer death in women globally. The involvement of several cellular pathways in carcinogenesis is still poorly understood. Here, we focused to evaluate the contributory role of Mismatch Repair (MMR) pathway genes-MLH1 and MSH2 in CACX and their association with chemo-tolerance of the disease. For this purpose, molecular profiles (expression/promoter methylation/deletion) of the genes were analysed in both normal cervical epithelium and tumour tissue, also validated in in-silico dataset as well. Later on, prognostic importance of the genes was identified through analysis of their methylation/expression status in plasma DNA of circulating tumour cells (CTCs) and cisplatin-tolerant CACX cell lines respectively. It was found that the expression profile of MLH1 and MSH2 genes was considerably reduced from undifferentiated basal-parabasal layers of normal cervical epithelium towards progression of the disease. Further analysis showed that frequent deletion [34-48%] and promoter methylation events [28-46%] of the genes were the plausible reasons for their reduced expression during tumorigenesis. Incidentally, the prevalence of MLH1 [32%] and MSH2 [27%] promoter methylation found in CTCs of plasma of the clinically advanced CACX patients implicated their prognostic importance of the disease. In addition, the patients having high alterations of those genes resulted in poor patient outcomes even after the therapy. In in-depth analysis of this result in cisplatin-tolerant CACX cell lines, we discovered that increased promoter methylation frequency of those genes at higher concentrations of cisplatin and gradual accumulation of the cells in the G2/M phase of the cell cycle were the rational causes for their reduced expression and MMR deficiency in the system. Hence, it is possible to conclude that the gradual down-regulation of MLH1 and MSH2 proteins may be a key event for MMR pathway inactivation in CACX. This might also be associated with chemo-tolerance and overall poor survival among the patients.
Collapse
Affiliation(s)
- Priyanka Dutta
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India
| | - Debolina Pal
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India
| | - Anup Roy
- Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata 700014, India
| | - Ranajit Kumar Mandal
- Department of Gynaecologic Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India.
| |
Collapse
|
|
12
|
Xie H, Rao X, Li J, Yao L, Ji Y, Zhang J, Wang H, Wang X, Li X. Diagnostic accuracy of extended HPV DNA genotyping and its application for risk-based cervical cancer screening strategy. Clin Chem Lab Med 2023; 61:2229-2236. [PMID: 37441737 DOI: 10.1515/cclm-2023-0440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023]
Abstract
OBJECTIVES To evaluate the consistency of 14 high-risk HPVs (hr-HPVs) detection between extended HPV DNA genotyping and a well-validated partial HPV genotyping kit, and to explore the diagnostic accuracy of risk stratification strategy based on extended HPV genotyping for cervical cancer (CC) screening. METHODS Baseline data from a clinical trial of recombinant HPV 9-valent vaccine in China was analyzed. All enrolled women aged 20-45 years received cervical cytology, HPV detection by extended and partial HPV genotyping kits. Those who met the indications would further receive colposcopy. The primary endpoints were cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). RESULTS A total of 8,000 women were enrolled between April 2020 and July 2020 and 83/33 cases were diagnosed as CIN2+/CIN3+. The overall agreement between the extended and partial HPV genotyping was 92.66 %. And the agreement further increased with the progression of lesions, which lead to similarly high sensitivity and negative predictive value of these kits. A stratified triage strategy of CC screening was constructed based on the immediate CIN2+/CIN3+ risk of specific HPV. Compared with the conventional HPV primary CC screening strategy, the risk-based strategy had higher specificity for CIN (CIN2+: 94.84 vs. 92.46 %, CIN3+: 96.05 vs. 91.92 %), and needed fewer colposcopies for detecting one cervical disease. CONCLUSIONS Extended HPV genotyping had good agreement with a well-validated partial HPV genotyping CC primary screening kit in hr-HPV detection. Extended HPV genotyping could facilitate risk-based stratified management strategy and improve the diagnostic accuracy of primary CC screening.
Collapse
Affiliation(s)
- Hongyu Xie
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, P.R. China
- Clinical Research Center, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Xuan Rao
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, P.R. China
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Junyan Li
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, Zhejiang, P.R. China
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Lifang Yao
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
- Department of Obstetrics and Gynecology, Shaoxing Maternal and Child Health Hospital, Shaoxing, Zhejiang, P.R. China
| | - Ying Ji
- Bovax Biotechnology Co., Ltd., Shanghai, P.R. China
| | - Juan Zhang
- Bovax Biotechnology Co., Ltd., Shanghai, P.R. China
| | - Hui Wang
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, P.R. China
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
- Cancer Research Institute of Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Xinyu Wang
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Xiao Li
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, P.R. China
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P.R. China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, Zhejiang, P.R. China
- Cancer Research Institute of Zhejiang University, Hangzhou, Zhejiang, P.R. China
| |
Collapse
|
|
13
|
Wang J, Li M, Zhao L, Zhou B, Chen H, Duan F, Wang G. Whole genome sequencing in high-grade cervical intraepithelial neoplasia patients from different ethnic groups in China. Medicine (Baltimore) 2023; 102:e35953. [PMID: 37960754 PMCID: PMC10637475 DOI: 10.1097/md.0000000000035953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
Cervical cancer (CC) is the fourth most common cancer in women worldwide. It develops through precancerous lesions (cervical intraepithelial neoplasia (CIN), graded from low-grade (CIN1) to high-grade (CIN2-3)). It is well established that precancerous and cancerous cervical lesions are caused by a persistent infection with high-risk types of the human papilloma virus (hrHPV). To have a deeper understanding of the pathogenesis of CIN and CC, we systematically analyzed the landscape of genomic alterations and HPV integration profiles in high-grade CIN2/3. We performed deep whole genome sequencing on exfoliated cervical cells and matched peripheral blood samples from a cohort of 51 Chinese patients (of whom 35 were HPV+) with high-grade CIN from 3 ethnic groups and constructed strict integrated workflow of genomic analysis. In addition, the HPV types and integration breakpoints in the exfoliated cervical cells from these patients were examined. Genomic analysis identified 6 significantly mutated genes (SMGs), including CDKN2A, PIK3CB, FAM20A, RABEP1, TMPRSS2 and SS18L1, in 51 CIN2/3 samples. As none of them had previously been identified as SMGs in the Cancer Genome Atlas cervical squamous cell carcinoma and endocervical adenocarcinoma (TCGA-CESC) cohort, future studies with larger sample size of CINs may be needed to validate our findings. Mutational signature analysis showed that mutational signatures of CINs were dramatically different from CCs, highlighting their different mutational processes and etiologies. Moreover, non-silent somatic mutations were detected in all of the CIN2/3 samples, and 88% of these mutations occurred in genes that also mutated in CCs of TCGA cohort. CIN2 samples had significantly less non-silent mutations than CIN3 samples (P = .0006). Gene ontology and pathway level analysis revealed that functions of mutated genes were significantly associated with tumorigenesis, thus these genes may be involved in the development and progression of CC. HPV integration breakpoints occurred in 28.6% of the CIN2/3 samples with HPV infection. Integrations of common high risk HPV types in CCs, including HPV16, 52, 58 and 68, also occurred in the CIN samples. Our results lay the groundwork for a deeper understanding of the molecular mechanisms underlying the pathogenesis of CC and pave the way for new tools for screening, diagnosis and treatment of cervical precancerous and cancerous lesions.
Collapse
Affiliation(s)
- Jingjing Wang
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
- Second Department of Production, Handan Central Hospital, Handan, Hebei Province, China
| | - Menghuan Li
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
- Department of Gynecology, People’s Hospital of Pingyu County, Zhumadian City, Henan Province, China
| | - Lixian Zhao
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
| | - Bingjie Zhou
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
- Maternity and Obstetrics Department of Fangshan District Maternity and Child Health Hospital of Beijing, Fangshan District of Beijing, China
| | - Huaqiu Chen
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
- Department of Laboratory, Xichang People’s Hospital, Sichuan Province, China
| | - Fuhui Duan
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
| | - Guangming Wang
- The First Affiliated Hospital of Dali University, Dali, Yunnan Province, China
| |
Collapse
|
|
14
|
Reijntjes B, Eising M, Kleppe M, Geuken E, Woolderink JM. The clinical relevance of excisional margins after large loop excision of the transformation zone for the persistence of cervical dysplasia. Int J Gynaecol Obstet 2023; 163:140-147. [PMID: 37243333 DOI: 10.1002/ijgo.14888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 04/12/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023]
Abstract
OBJECTIVE A new guideline on population-screening cervical cytology was introduced to improve diagnosis and management of (pre-)malignant cervical lesions. Subsequently, more colposcopies and more large loop excision of the transformation zone (LLETZ) were performed. There is little information about the relevance of positive margins for cervical intraepithelial neoplasia (CIN) after LLETZ. This study assesses the clinical relevance of margins on the presence of CIN. METHODS In this retrospective study, 567 women who had undergone LLETZ due to cervical dysplasia between January 2017 and December 2019 in Martini Hospital Groningen were included. The primary outcome was the persistence of cervical dysplasia (Pap ≥2) in relation to excisional margins. A χ2 test was performed and hazard ratios with 95% confident intervals (CIs) were reported. RESULTS After median follow-up of 14 months, 9% (N = 28) with affected margins and 4% (N = 9) with clear margins had persistent cervical dysplasia (P = 0.044). Positive human papillomavirus (HPV) status was an independent risk factor (hazard ratio [HR] 8.97, 95% confidence interval [CI] 4.19-19.22). Women with affected margins and of older age were less prone to clear HPV (P < 0.001). CONCLUSION Women treated with LLETZ for cervical dysplasia show favorable long-term outcomes, with low residual rate. High-risk HPV combined with excisional margin status and age appears to be an adequate risk stratification and individualized management might be based on these factors.
Collapse
Affiliation(s)
- Bianca Reijntjes
- Department of Obstetrics and Gynecology, Martini Hospital Groningen, Groningen, the Netherlands
| | - Manon Eising
- Department of Obstetrics and Gynecology, Martini Hospital Groningen, Groningen, the Netherlands
| | - Marjolein Kleppe
- Department of Obstetrics and Gynecology, Martini Hospital Groningen, Groningen, the Netherlands
| | - Erwin Geuken
- Department of Pathology, Martini Hospital Groningen, Groningen, the Netherlands
| | - Jorien M Woolderink
- Department of Obstetrics and Gynecology, Martini Hospital Groningen, Groningen, the Netherlands
| |
Collapse
|
|
15
|
Paul A, Dutta P, Basu K. Assessment and clinicopathological correlation of p16 expression in cervical squamous cell carcinoma of Indian population: Diagnostic implications. J Cancer Res Ther 2023; 19:2012-2017. [PMID: 38376311 DOI: 10.4103/jcrt.jcrt_753_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/22/2022] [Indexed: 02/21/2024]
Abstract
BACKGROUND Our aim was to assess the p16 expression in normal cervical epithelium and cervical lesions and how it correlated with HPV oncoprotein E7 and other etiological parameters of cervical cancer. METHODS For this purpose, we analyzed protein expression of p16 and E7 oncoprotein in total 20 normal cervical epithelium tissue (as control) and 62 cervical lesions. Next, the result was correlated with different clinico-pathological parameters. RESULTS Out of 62 cases of cervical lesions, we found around 75%-100% of the cervical lesion samples exhibited E7 nuclear protein expression, whereas around 33.33%-75% samples were p16 positive. On the other hand, p16 expression showed strong association with E7 oncoprotein and other clinico-pathological parameters (like high parity, early age of sextual debut) in the same set of samples of our study. CONCLUSION We concluded that overexpression of p16 is very practical and can be readily implemented in most diagnostic pathology laboratories.
Collapse
Affiliation(s)
- Arkadip Paul
- Department of Pathology, Murshidabad Medical College and Hospital (MSDMCH), Berhampore, West Bengal, India
| | - Priyanka Dutta
- Department of Oncogene Regulation Unit, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, India
| | - Keya Basu
- Department of Pathology, KPC Medical College, Kolkata, West Bengal, India
| |
Collapse
|
|
16
|
Lee J, Lee HJ. Do Concurrent Multiple Infections with High-Risk HPVs Carry a More Malignant Potential than a Single Infection in the Uterine Cervix? J Clin Med 2023; 12:6155. [PMID: 37834799 PMCID: PMC10573320 DOI: 10.3390/jcm12196155] [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: 08/10/2023] [Revised: 09/11/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
The high-risk human papillomavirus (HR-HPV) has been known as the most important carcinogen in uterine cervical carcinoma. However, there is limited evidence of the malignant potential of these concurrent multiple infections. This study included women who had undergone cervical conization. They underwent an HPV test by cervical swab within 12 months before the surgery. They were divided into two groups: one with a single infection with HR-HPV16 and the other with concurrent multiple infections with HR-HPVs, including genotype 16. Pathologic examination classified cases as CIS+ to assess and compare the malignant potential in both groups, including carcinoma in situ (CIS) and invasive carcinoma. Of the 220 patients infected with HR-HPV16, the single infection group consisted of 120 patients (54.5%), whereas the concurrent multiple infections consisted of 100 (45.5%) patients. The rates of HSIL were significantly higher in the concurrent multiple infection group. However, the odds ratio for CIS+ did not show a significant difference between both groups (1.417, 95% CI = 0.831-2.414, p = 0.200). The malignant potential was not significantly different between concurrent multiple infections with HR-HPVs, including 16, and a single infection with 16 in Korean women.
Collapse
Affiliation(s)
| | - Hyun Jung Lee
- Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea;
| |
Collapse
|
|
17
|
Taghavi K, Zhao F, Downham L, Baena A, Basu P. Molecular triaging options for women testing HPV positive with self-collected samples. Front Oncol 2023; 13:1243888. [PMID: 37810963 PMCID: PMC10560038 DOI: 10.3389/fonc.2023.1243888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 08/28/2023] [Indexed: 10/10/2023] Open
Abstract
We review developments in molecular triaging options for women who test positive for high-risk human papillomavirus (hrHPV) on self-collected samples in the context of cervical cancer elimination. The World Health Organization (WHO) recommends hrHPV screening as the primary test for cervical screening due to its high sensitivity compared to other screening tests. However, when hrHPV testing is used alone for treatment decisions, a proportion of women of childbearing age receive unnecessary treatments. This provides the incentive to optimize screening regimes to minimize the risk of overtreatment in women of reproductive age. Molecular biomarkers can potentially enhance the accuracy and efficiency of screening and triage. HrHPV testing is currently the only screening test that allows triage with molecular methods using the same sample. Additionally, offering self-collected hrHPV tests to women has been reported to increase screening coverage. This creates an opportunity to focus health resources on linking screen-positive women to diagnosis and treatment. Adding an additional test to the screening algorithm (a triage test) may improve the test's positive predictive value (PPV) and offer a better balance of benefits and risks for women. Conventional triage methods like cytology and visual inspection with acetic acid (VIA) cannot be performed on self-collected samples and require additional clinic visits and subjective interpretations. Molecular triaging using methods like partial and extended genotyping, methylation tests, detection of E6/E7 proteins, and hrHPV viral load in the same sample as the hrHPV test may improve the prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and invasive cancer, offering more precise, efficient, and cost-effective screening regimes. More research is needed to determine if self-collected samples are effective and cost-efficient for diverse populations and in comparison to other triage methods. The implementation of molecular triaging could improve screening accuracy and reduce the need for multiple clinical visits. These important factors play a crucial role in achieving the global goal of eliminating cervical cancer as a public health problem.
Collapse
Affiliation(s)
- Katayoun Taghavi
- Early Detection, Prevention and Infections Branch, International Agency For Research On Cancer (IARC), Lyon, France
| | - Fanghui Zhao
- Department of Cancer Epidemiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Laura Downham
- Early Detection, Prevention and Infections Branch, International Agency For Research On Cancer (IARC), Lyon, France
| | - Armando Baena
- Early Detection, Prevention and Infections Branch, International Agency For Research On Cancer (IARC), Lyon, France
| | - Partha Basu
- Early Detection, Prevention and Infections Branch, International Agency For Research On Cancer (IARC), Lyon, France
| |
Collapse
|
|
18
|
Xu Y, Sun Y, Song X, Ren J. The mechanisms and diagnostic potential of lncRNAs, miRNAs, and their related signaling pathways in cervical cancer. Front Cell Dev Biol 2023; 11:1170059. [PMID: 37215076 PMCID: PMC10192553 DOI: 10.3389/fcell.2023.1170059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 05/24/2023] Open
Abstract
Cervical cancer (CC), the fourth most prevalent type of cancer among women worldwide, is associated with high rates of morbidity and mortality. Due to the long period of latency in CC, most patients are already in the middle to late stages when initially diagnosed, which greatly reduces the clinical cure rate and quality of survival, thus resulting in poor outcomes. In recent years, with continuous exploration in the fields of bioinformatics and molecules, it has been found that ncRNAs, including miRNAs and lncRNAs, without the ability to translate proteins are capable of activating or inhibiting certain signaling pathways by targeting and modulating the level of expression of proteins involved in these signaling pathways. ncRNAs play important roles in assisting with diagnosis, drug administration, and prediction of prognosis during CC progression. As an entry point, the mechanisms of interaction between miRNAs, lncRNAs, and signaling pathways have long been a focus in basic research relating to CC, and numerous experimental studies have confirmed the close relationship of miRNAs, lncRNAs, and signaling pathways with CC development. Against this background, we summarize the latest advances in the involvement of lncRNA- and miRNA-related signaling pathways in the development of CC to provide guidance for CC treatment.
Collapse
|
|
19
|
Ma KSK, Chin NC, Tu TY, Wu YC, Yip HT, Wei JCC, Chang RI. Human Papillomavirus Infections and Increased Risk of Incident Osteoporosis: A Nationwide Population-Based Cohort Study. Viruses 2023; 15:v15041021. [PMID: 37113002 PMCID: PMC10143035 DOI: 10.3390/v15041021] [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: 12/14/2022] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 04/29/2023] Open
Abstract
Patients with viral infections are susceptible to osteoporosis. This cohort study investigated the correlation between human papillomavirus (HPV) infections and the risk of osteoporosis via 12,936 patients with new-onset HPV infections and propensity score-matched non-HPV controls enrolled in Taiwan. The primary endpoint was incident osteoporosis following HPV infections. Cox proportional hazards regression analysis and the Kaplan-Meier method was used to determine the effect of HPV infections on the risk of osteoporosis. Patients with HPV infections presented with a significantly high risk of osteoporosis (adjusted hazard ratio, aHR = 1.32, 95% CI = 1.06-1.65) after adjusting for sex, age, comorbidities and co-medications. Subgroup analysis provided that populations at risk of HPV-associated osteoporosis were females (aHR = 1.33; 95% CI = 1.04-1.71), those aged between 60 and 80 years (aHR = 1.45, 95% CI = 1.01-2.08 for patients aged 60-70; aHR = 1.51; 95% CI = 1.07-2.12 for patients aged 70-80), and patients with long-term use of glucocorticoids (aHR = 2.17; 95% CI = 1.11-4.22). HPV-infected patients who did not receive treatments for HPV infections were at a greater risk (aHR = 1.40; 95% CI = 1.09-1.80) of osteoporosis, while the risk of osteoporosis in those who received treatments for HPV infections did not reach statistical significance (aHR = 1.14; 95% CI = 0.78-1.66). Patients with HPV infections presented with a high risk of subsequent osteoporosis. Treatments for HPV infections attenuated the risk of HPV-associated osteoporosis.
Collapse
Affiliation(s)
- Kevin Sheng-Kai Ma
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Orthodontics and Dentofacial Orthopedics, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ning-Chien Chin
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Ting-Yu Tu
- Department of Orthopedics, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
| | - Yao-Cheng Wu
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Hei-Tung Yip
- Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Ren-In Chang
- Department of Recreation Sports Management, Tajen University, Pingtung 907, Taiwan
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
| |
Collapse
|
|
20
|
Riepler L, Frommelt LS, Wilmschen-Tober S, Mbuya W, Held K, Volland A, von Laer D, Geldmacher C, Kimpel J. Therapeutic efficacy of a VSV-GP-based human papilloma virus vaccine in a murine cancer model. J Mol Biol 2023; 435:168096. [PMID: 37086948 DOI: 10.1016/j.jmb.2023.168096] [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: 11/22/2022] [Revised: 02/21/2023] [Accepted: 04/10/2023] [Indexed: 04/24/2023]
Abstract
Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3' end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP's genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.
Collapse
Affiliation(s)
- Lydia Riepler
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Laura-Sophie Frommelt
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Sarah Wilmschen-Tober
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Wilbert Mbuya
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU, 80802 Munich, Germany; National Institute for Medical Research-Mbeya Medical Research Centre (NIMR-MMRC), Mbeya, Tanzania
| | - Kathrin Held
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU, 80802 Munich, Germany; German Center for Infection Research (DZIF), Partner site Munich, 80802 Munich, Germany
| | - André Volland
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Dorothee von Laer
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Christof Geldmacher
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU, 80802 Munich, Germany; German Center for Infection Research (DZIF), Partner site Munich, 80802 Munich, Germany
| | - Janine Kimpel
- Department of Hygiene, Microbiology and Public Health, Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
| |
Collapse
|
|
21
|
Chen R, Zhang R, Zhang M, Liu S, Xie M, Yang Z, Shi Q, Chen H, Xiong H, Wang N, Jiang Q. CIN grades possessing different HPV RNA location patterns and RNAscope is helpful tool for distinguishing squamous intraepithelial lesions in difficult cervical cases. Diagn Pathol 2023; 18:23. [PMID: 36797728 PMCID: PMC9933306 DOI: 10.1186/s13000-023-01308-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND AND OBJECTIVES The precise grading and characterization of cervical intraepithelial neoplasia (CIN) has been the focus of pathologists for a long time. This study aimed to explore known strategies for the grading of CINs. METHODS After routine H&E review, 85 lesions graded CIN 1, 2, or 3 were investigated primarily by HPV RNAscope to detect HR-HPV and LR-HPV, in combination with an HPV-DNA test and P16/Ki67 immunohistochemistry (IHC). Then, the 85 cases were divided into a control group (49 cases) and a test group (36 cases). The former consisted of cases with consistency between morphology, HPV DNA detection and P16/Ki67 IHC. We used them to evaluate HPV RNA distribution patterns in CINs of different grades. The latter were ambiguous cases in which pathologists could not confirm the diagnosis because of inconsistencies between morphology, HPV DNA detection and P16/Ki67 IHC. We reassessed them by comparison to the pattern in the control group. RESULTS The expression patterns of HPV mRNA signals were different in different CIN lesions. LSIL/CIN1 lesions were mostly expressed in superficial epithelium with diffuse clustered nuclear or cytoplasmic staining; HSIL/CIN2 were characterised by nuclear/cytoplasmic punctate or diffuse cluster nuclear staining in the mid-surface layer, and scattered nuclear/cytoplasmic punctate staining in basal and parabasal cells; whereas HSIL/CIN3 showed full-thickness nucleus/cytoplasmic scattered staining with a punctate pattern. According to the staining pattern, we corrected the diagnosis of 22 cases (22/36, 61.1%). CONCLUSION Because of its distinct location pattern, HPV RNAscope has obvious advantages over the HPV-DNA test, and combined with P16/Ki67 IHC, it can help pathologists correctly grade CIN. In addition, it can effectively discriminate true CIN from normal or CIN mimic lesions, such as immature squamous metaplasia, atrophy, and inflammatory/reactive changes. Therefore, HPV RNAscope is a valuable auxiliary diagnostic test to avoid the overtreatment and undertreatment of CIN lesions.
Collapse
Affiliation(s)
- Ruichao Chen
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.484195.5Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Renchao Zhang
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.410726.60000 0004 1797 8419Department of Pathology, University of Chinese Academy of Sciences-Shenzhen Hospital (Guang Ming), Shenzhen, China
| | - Minfen Zhang
- grid.508008.50000 0004 4910 8370Department of Pathology, The First Hospital of Changsha, Hunan, China
| | - Shaoyan Liu
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.484195.5Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Mingyu Xie
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhongfeng Yang
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Quan Shi
- grid.413428.80000 0004 1757 8466Department of Pathology, Guangzhou Women And Children’s Medical Center, Guangzhou, China
| | - Hui Chen
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.484195.5Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Hanzhen Xiong
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.484195.5Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Na Wang
- grid.417009.b0000 0004 1758 4591Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China ,grid.484195.5Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Qingping Jiang
- Department of Pathology, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China.
| |
Collapse
|
|
22
|
Mazurek AM, Rutkowski TW. Practical Application of Circulating Tumor-Related DNA of Human Papillomavirus in Liquid Biopsy to Evaluate the Molecular Response in Patients with Oropharyngeal Cancer. Cancers (Basel) 2023; 15:1047. [PMID: 36831390 PMCID: PMC9953792 DOI: 10.3390/cancers15041047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.
Collapse
Affiliation(s)
- Agnieszka M. Mazurek
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Tomasz W. Rutkowski
- I Radiation and Clinical Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
| |
Collapse
|
|
23
|
Dutta P, Basu M, Roy A, Mandal RK, Panda CK. High nuclear expression of DNMT1 in correlation with inactivation of TET1 portray worst prognosis among the cervical carcinoma patients: clinical implications. J Mol Histol 2023; 54:89-102. [PMID: 36692670 DOI: 10.1007/s10735-023-10114-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/15/2023] [Indexed: 01/25/2023]
Abstract
In this study, we aimed to understand the interplay of the epigenetic modifier genes DNMT1 and TET1 along with HPV infection in the cervical epithelium and how it changes during tumorigenesis. For this purpose, initially the bioinformatical analysis (methylation and expression profile) of DNMT1 and TET1 was analyzed in the TCGA dataset. Next genetic (deletion) and epigenetic profiling (promoter methylation) of DNMT1 and TET1 were done in our sample pool and also validated in CACX cell lines as well. The results were further correlated with different clinicopathological parameters. Our data revealed that HPV infection in basal/parabasal layers of cervical epithelium actually disrupts the epigenetic homeostasis of DNMT1 and TET1 proteins which ultimately leads to the high expression of DNMT1 along with further reduction in TET1 protein during the development of carcinoma. Further, in-depth look into the results revealed that comparatively low methylation frequency of DNMT1 coupled with high promoter methylation and deletion frequency [22-46%] of TET1 were the plausible reasons of their antagonistic expression profile during the progression of the disease. Interestingly, the prevalence of DNMT1 [9.1%] and TET1 promoter methylation [22.7%] found in both the plasma DNA of the respective CACX patients implicated its diagnostic importance in this study. Lastly, molecular alteration of TET1 alone or in combination with DNMT1 showed the worst overall survival among the patients. Hence, it may be concluded that an inverse molecular profile of DNMT1 and TET1 genes seen in the proliferative basal-parabasal layers of the cervical epithelium was aggravated during the development of CACX along with genetic and epigenetic changes due to HPV infection.
Collapse
Affiliation(s)
- Priyanka Dutta
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Mukta Basu
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Anup Roy
- Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, 700014, India
| | - Ranajit Kumar Mandal
- Department of Gynaecologic Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India.
| |
Collapse
|
|
24
|
Bhavya, Rajaram S, Gupta B, Banerjee BD, Arora VK, Thakur G, Jain S. PAX1 Methylation Status in Cervical Scrapes as Novel Diagnostic Biomarker in CIN 2/3 and Invasive Squamous Cell Carcinoma. J Obstet Gynaecol India 2022; 72:522-528. [PMID: 36506900 PMCID: PMC9732169 DOI: 10.1007/s13224-022-01680-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/28/2022] [Indexed: 12/13/2022] Open
Abstract
Objectives DNA methylation of paired box-1 (PAX-1) gene has been shown to be a potential biomarker for the detection of high-grade cervical intra-epithelial neoplasia (CIN) and invasive cervical cancer. The objective of this pilot study was to quantify and compare methylation percentage of PAX1 gene in benign cervical lesion, pre-invasive and invasive cervical cancer. Methods A total of 200 screen positive women (VIA, VILI and Pap test) underwent colposcopy. Cervical scrapes taken were taken and stored for DNA analysis and PAX 1 methylation status. Women with Swede score of 5 or more (n = 98) were biopsied. Cervical scrapes and biopsy were taken from women with obvious cervical growth (n = 14), without prior colposcopy. Sixty women were recruited to the study and allocated into three groups on the basis of histopathology, i.e., benign cervix (Group 1; n = 20), CIN 2/3 (Group 2; n = 20) and invasive cervical carcinoma (Group; n = 20). PAX 1 methylation percentage was calculated from the DNA extracted from the cervical scrapes of the women recruited. Results The mean PAX1 methylation percentage in benign lesions, CIN 2/3 and invasive cancer was 9.58% (SD ± 2.37%), 18.21% (SD ± 2.67%) and 24.34% (SD ± 4.09%), respectively, with p-value of < 0.001. Conclusions PAX 1 gene methylation has a promising role in identifying high-grade lesions and invasive cancer.
Collapse
Affiliation(s)
- Bhavya
- Department of Obstetrics & Gynaecology, UCMS & GTB Hospital, A-318, Mangal Apartments, Vasundhara Enclave, Delhi, India
| | | | - Bindiya Gupta
- Department of Obstetrics & Gynaecology, UCMS & GTB Hospital, A-318, Mangal Apartments, Vasundhara Enclave, Delhi, India
| | - B. D. Banerjee
- Department of Biochemistry, UCMS & GTB Hospital, Delhi, India
| | | | - Gaurav Thakur
- Department of Biochemistry, UCMS & GTB Hospital, Delhi, India
| | - Sandhya Jain
- Department of Obstetrics & Gynaecology, UCMS & GTB Hospital, A-318, Mangal Apartments, Vasundhara Enclave, Delhi, India
| |
Collapse
|
|
25
|
Zhang YR, Zheng PS. NEK2 inactivates the Hippo pathway to advance the proliferation of cervical cancer cells by cooperating with STRIPAK complexes. Cancer Lett 2022; 549:215917. [PMID: 36115593 DOI: 10.1016/j.canlet.2022.215917] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/19/2022]
Abstract
The never in mitosis gene A (NIMA)-related kinase 2 (NEK2) protein has been reported to be an oncoprotein that plays different oncogenic roles in multiple cancers. Here, we confirmed that NEK2 highly expressed in cervical cancer cells rather than in normal epithelial basal layer cells in cervical tissues and correlated with worse outcomes. We also demonstrated that NEK2 promoted the in vivo growth of subcutaneous xenograft tumors stemming from cervical cancer cells and the in vitro cell proliferation by decreasing Ser127-phosphorylation of the YAP protein retained in the cytoplasm while increasing the levels of active nucleus-associated YAP protein, which was followed by increases in the targeted proteins CTGF, CYR61 and GLI2. Furthermore, the Hippo signaling pathway was inactivated in manipulated NEK2-overexpressing cervical cancer cells by regulating the levels of MST1/2 dephosphorylation. Additionally, mass spectrometric sequencing and bilateral coimmunoprecipitation were employed suggested that NEK2 acted at an early upstream step to promote dephosphorylation of MST2 and inactivate the Hippo signaling cascade by cooperating with STRIPAK complexes. We conjecture that NEK2 may be a future target for cervical cancer therapy.
Collapse
Affiliation(s)
- Yan-Ru Zhang
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China
| | - Peng-Sheng Zheng
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China; Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Xi'an, 710061, Shaanxi, PR China.
| |
Collapse
|
|
26
|
Zibako P, Hlongwa M, Tsikai N, Manyame S, Ginindza TG. Mapping Evidence on Management of Cervical Cancer in Sub-Saharan Africa: Scoping Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:9207. [PMID: 35954564 PMCID: PMC9367747 DOI: 10.3390/ijerph19159207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023]
Abstract
Cervical cancer (CC) is the most common viral infection of the reproductive tract and in Sub-Saharan Africa (SSA), its morbidity and mortality rates are high. The aim of this review was to map evidence on CC management in SSA. The scoping review was conducted in accordance with Arksey and O'Malley's scoping review framework. The review included studies on different aspects of CC management. The review was also done following the steps and guidelines outlined in the PRISMA-Extension for Scoping Reviews (PRISMA-ScR) checklist. The following databases were searched: PubMed, EBSCOhost, Scopus and Cochrane Database of Systematic Review. A total of 1121 studies were retrieved and 49 which were eligible for data extraction were included in the review. The studies were classifiable in 5 groups: 14 (28.57%) were on barriers to CC screening, 10 (20.41%) on factors associated with late-stage presentation at diagnosis, 11 (22.45%) on status of radiotherapy, 4 (8.20%) on status of chemotherapy and 10 (20.41%) on factors associated with high HPV coverage. High HPV vaccine coverage can be achieved using the class school-based strategy with opt-out consent form process. Barriers to CC screening uptake included lack of knowledge and awareness and unavailability of screening services. The reasons for late-stage presentation at diagnosis were unavailability of screening services, delaying whilst using complementary and alternative medicines and poor referral systems. The challenges in chemotherapy included unavailability and affordability, low survival rates, treatment interruption due to stock-outs as well as late presentation. Major challenges on radiotherapy were unavailability of radiotherapy, treatment interruption due to financial constraints, and machine breakdown and low quality of life. A gap in understanding the status of CC management in SSA has been revealed by the study implying that, without full knowledge of the extent of CC management, the challenges and opportunities, it will be difficult to reduce infection, improve treatment and palliative care. Research projects assessing knowledge, attitude and practice of those in immediate care of girls at vaccination age, situational analysis with health professionals and views of patients themselves is important to guide CC management practice.
Collapse
Affiliation(s)
- Petmore Zibako
- Discipline of Public Health, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa; (M.H.); (T.G.G.)
| | - Mbuzeleni Hlongwa
- Discipline of Public Health, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa; (M.H.); (T.G.G.)
- Burden of Disease Research Unit, South African Medical Research Council, Cape Town 7505, South Africa
| | - Nomsa Tsikai
- College of Health Sciences, University of Zimbabwe, MT Pleasant, Harare P.O. Box MP167, Zimbabwe; (N.T.); (S.M.)
| | - Sarah Manyame
- College of Health Sciences, University of Zimbabwe, MT Pleasant, Harare P.O. Box MP167, Zimbabwe; (N.T.); (S.M.)
| | - Themba G. Ginindza
- Discipline of Public Health, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4000, South Africa; (M.H.); (T.G.G.)
- Cancer & Infectious Diseases Epidemiology Research Unit (CIDERU), College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| |
Collapse
|
|
27
|
Vieira GV, Somera dos Santos F, Lepique AP, da Fonseca CK, Innocentini LMAR, Braz-Silva PH, Quintana SM, Sales KU. Proteases and HPV-Induced Carcinogenesis. Cancers (Basel) 2022; 14:cancers14133038. [PMID: 35804810 PMCID: PMC9264903 DOI: 10.3390/cancers14133038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Human papillomavirus (HPV) infection is a sexually transmitted disease with high prevalence worldwide. Although most HPV infections do not lead to cancer, some HPV types are correlated with the majority of cervical cancers, and with some anogenital and oropharyngeal cancers. Moreover, enzymes known as proteases play an essential role in the pathogenic process in HPV-induced carcinogenesis. This review highlights the role of proteases and recent epidemiological data regarding HPV-dependent carcinogenesis. Abstract Persistent infection with Human papillomavirus (HPV) is the main etiologic factor for pre-malignant and malignant cervical lesions. Moreover, HPV is also associated with oropharynx and other anogenital carcinomas. Cancer-causing HPV viruses classified as group 1 carcinogens include 12 HPV types, with HPV 16 and 18 being the most prevalent. High-risk HPVs express two oncoproteins, E6 and E7, the products of which are responsible for the inhibition of p53 and pRB proteins, respectively, in human keratinocytes and cellular immortalization. p53 and pRB are pleiotropic proteins that regulate the activity of several signaling pathways and gene expression. Among the important factors that are augmented in HPV-mediated carcinogenesis, proteases not only control processes involved in cellular carcinogenesis but also control the microenvironment. For instance, genetic polymorphisms of matrix metalloproteinase 1 (MMP-1) are associated with carcinoma invasiveness. Similarly, the serine protease inhibitors hepatocyte growth factor activator inhibitor-1 (HAI-1) and -2 (HAI-2) have been identified as prognostic markers for HPV-dependent cervical carcinomas. This review highlights the most crucial mechanisms involved in HPV-dependent carcinogenesis, and includes a section on the proteolytic cascades that are important for the progression of this disease and their impact on patient health, treatment, and survival.
Collapse
Affiliation(s)
- Gabriel Viliod Vieira
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
| | - Fernanda Somera dos Santos
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (F.S.d.S.); (S.M.Q.)
| | - Ana Paula Lepique
- Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo 05508-000, SP, Brazil;
| | - Carol Kobori da Fonseca
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
| | - Lara Maria Alencar Ramos Innocentini
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
- Clinical Hospital of Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, SP, Brazil
| | - Paulo Henrique Braz-Silva
- Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo 05508-000, SP, Brazil;
- Laboratory of Virology, Institute of Tropical Medicine of Sao Paulo, School of Medicine, University of Sao Paulo, Sao Paulo 05403-000, SP, Brazil
| | - Silvana Maria Quintana
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (F.S.d.S.); (S.M.Q.)
| | - Katiuchia Uzzun Sales
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
- Correspondence: ; Tel.: +55-16-3315-9113
| |
Collapse
|
|
28
|
De SK. Tisotumab vedotin; First FDA Approved Antibody-drug Conjugate for Cervical Cancer. Anticancer Agents Med Chem 2022; 22:2808-2810. [DOI: 10.2174/1871520622666220421095240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/02/2022] [Accepted: 03/02/2022] [Indexed: 11/22/2022]
|
|
29
|
Yang Q, Al-Hendy A. The Regulatory Functions and the Mechanisms of Long Non-Coding RNAs in Cervical Cancer. Cells 2022; 11:cells11071149. [PMID: 35406713 PMCID: PMC8998012 DOI: 10.3390/cells11071149] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/25/2022] [Accepted: 03/27/2022] [Indexed: 12/11/2022] Open
Abstract
Cervical cancer is one of the leading causes of death in gynecology cancer worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer. Still, other factors also contribute to cervical cancer development because these cancers commonly arise decades after initial exposure to HPV. So far, the molecular mechanisms underlying the pathogenesis of cervical cancer are still quite limited, and a knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve cervical cancer patient outcomes. Long non-coding RNAs (lncRNAs) have been increasingly shown to be involved in gene regulation, and the relevant role of lncRNAs in cervical cancer has recently been investigated. In this review, we summarize the recent progress in ascertaining the biological functions of lncRNAs in cervical cancer from the perspective of cervical cancer proliferation, invasion, and metastasis. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of lncRNAs in the pathogenesis of cervical cancer. Comprehensive and deeper insights into lncRNA-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with cervical cancer.
Collapse
|
|
30
|
Wang H, He Z, Han X, Zhang D, Zhang S. Prediction value with a novel and accurate tissue-based human papillomavirus detection method in low-grade squamous intraepithelial lesions. Cancer Med 2022; 11:2576-2587. [PMID: 35343653 PMCID: PMC9249975 DOI: 10.1002/cam4.4634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/10/2022] [Accepted: 02/02/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The progression rate from CIN1 to CIN3 is 9.0% and that for invasive cancer is 1.0%. The large majority of CIN1 lesions regress spontaneously, and the treatment of CIN1 is still controversial. AIMS The aim of this study is to investigate the responsible HPV genotype in the low-grade SILs, then to predict the presence of high-grade SILs, and determine whether further treatment is needed. METHODS We use the methods of manual microdissection with FFPE tissue specimens and the E6/E7 uniplex polymerase chain reaction (PCR) to detect HPV in the lesions. RESULTS The HPV test was performed on 72 biopsy tissue specimens, and 55 (76.4%, 55/72) of them were HPV positive. Nine (16.4%, 9/55) of them escalated to CIN2 after LEEP or cervical conization, and 46 (83.6%, 46/55) were still CIN1. There were 17 (23.6%, 17/72) cases with HPV-negative results in cervical biopsy tissues. HPV test of cervical biopsy diagnosed with CIN1 has a positive predictive value of 16.4% in the presence of CIN2 or higher lesions, a negative predictive value of 94.1%, a specificity of 25.8%, and a sensitivity of 90.0%. HPV test of cervical biopsy tissues for the prediction of HPV infection in LEEP or cone surgery tissues had a positive predictive value of 80.0%, a negative predictive value of 82.3%, a specificity of 56.0%, and a sensitivity of 93.6%. CONCLUSIONS It is the first time that we have detected HPV genotype in the low-grade SILs by the methods of manual microdissection with FFPE tissue specimens and the E6/E7 uniplex PCR. Patients with cervical biopsy tissue diagnosed with CIN1 and with a negative or only low-risk HPV type result can be considered for follow-up. Conversely, in cases of cervical biopsy tissue diagnosed with CIN1 positive for high-risk HPV, surgery or a close follow-up program can be selected.
Collapse
Affiliation(s)
- He Wang
- Department of Obstetrics, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zheng He
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue Han
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Deyu Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shitai Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
31
|
Muntinga CLP, de Vos van Steenwijk PJ, Bekkers RLM, van Esch EMG. Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy. J Clin Med 2022; 11:jcm11051432. [PMID: 35268523 PMCID: PMC8910829 DOI: 10.3390/jcm11051432] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/10/2022] Open
Abstract
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs.
Collapse
Affiliation(s)
- Caroline L. P. Muntinga
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Peggy J. de Vos van Steenwijk
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
- Department of Gynecology and Obstetrics, Maastricht Universitair Medisch Centrum, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Ruud L. M. Bekkers
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Edith M. G. van Esch
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- Correspondence: ; Tel.: +31-402-399-111
| |
Collapse
|
|
32
|
Regauer S, Reich O, Kashofer K. HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions. Am J Surg Pathol 2022; 46:147-158. [PMID: 34387215 DOI: 10.1097/pas.0000000000001778] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.
Collapse
Affiliation(s)
| | - Olaf Reich
- Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria
| | | |
Collapse
|
|
33
|
Song C, Lee Y, Kim S. Bioinformatic Analysis for the Prognostic Implication of Genes Encoding Epithelial Sodium Channel in Cervical Cancer. Int J Gen Med 2022; 15:1777-1787. [PMID: 35210842 PMCID: PMC8863188 DOI: 10.2147/ijgm.s346222] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/08/2022] [Indexed: 12/22/2022] Open
Abstract
Background Cervical cancer is one of the leading causes of death in women. Among the sodium ion channels associated with cancer development, voltage gated sodium channel plays an important role in pathophysiology of cervical cancer; however, the clinicopathological implication of epithelial sodium channel (ENaC) has not been explored. Purpose This study focused on identifying dysregulation of ENaC encoding genes, including SCNN1A, SCNN1B, and SCNN1G, and their relationship with clinicopathologic features in cervical cancer patients. Materials and Methods RNA sequencing data of ENaC-encoding genes, clinicopathologic data, and survival data of cervical cancer patients were obtained from The Cancer Genome Atlas cohort. Microarray data of ENaC-encoding genes were obtained from Gene Expression Omnibus datasets: GSE6791 and GSE63514. Results The expression levels of SCNN1A, SCNN1B, and SCNN1G were positively correlated with each other. SCNN1A, SCNN1B, and SCNN1G are significantly overexpressed in normal tissues than in tumor tissues. Survival analysis showed that simultaneous overexpression of all three genes associated with better overall survival (OS). Each overexpression of SCNN1B and SCNN1G was significantly associated with better OS. Moreover, each expression level of SCNN1A, SCNN1B, and SCNN1G was negatively correlated with histologic grade of tumor. Conclusion ENaC-encoding genes might be potential biological markers to better predict survival outcomes in cervical cancer patients.
Collapse
Affiliation(s)
- Changho Song
- Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea
| | - Yongho Lee
- Department of Anesthesiology and Pain Medicine, Keimyung University Dongsan Hospital, Daegu, 42601, Republic of Korea
| | - Shin Kim
- Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea
- Institute of Medical Science, Keimyung University, Daegu, 42601, Republic of Korea
- Institute for Cancer Research, Keimyung University Dongsan Medical Center, Daegu, 42601, Republic of Korea
- Correspondence: Shin Kim, 1095 Dalgubeol-Daero, Dalseo-gu, Daegu, 42601, Republic of Korea, Tel +82-53-258-7359, Fax +82-53-258-7355, Email
| |
Collapse
|
|
34
|
Yang S, Feng T, Li H. KLF5, a Novel Therapeutic Target in Squamous Cell Carcinoma. DNA Cell Biol 2021; 40:1503-1512. [PMID: 34931868 DOI: 10.1089/dna.2021.0674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Squamous cell carcinomas (SCCs) are the most common ectodermal cancers, and result in more than 300,000 deaths per year. The Krüppel-like family of transcription factors play a critical role in cancer pathogenesis. The Krüppel-like factor 5 gene (KLF5), which is a member of Krüppel-like family, has been reported to promote cancer cell proliferation and tumorigenesis. In this review, we discuss the roles of KLF5 in different SCCs and the mechanisms by which KLF5 transcriptionally regulates its target gene expression in the pathogenesis and progression of SCCs. Due to its significant functions in cell proliferation and differentiation, KLF5 could be a novel diagnostic biomarker and therapeutic target for the treatment of SCCs.
Collapse
Affiliation(s)
- Shuo Yang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Ting Feng
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Hong Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
35
|
Wang Y, Liu R, Liao J, Jiang L, Jeong GH, Zhou L, Polite M, Duong D, Seyfried NT, Wang H, Kiyokawa H, Yin J. Orthogonal ubiquitin transfer reveals human papillomavirus E6 downregulates nuclear transport to disarm interferon-γ dependent apoptosis of cervical cancer cells. FASEB J 2021; 35:e21986. [PMID: 34662469 DOI: 10.1096/fj.202101232rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 02/05/2023]
Abstract
The E6 protein of the human papillomavirus (HPV) underpins important protein interaction networks between the virus and host to promote viral infection. Through its interaction with E6AP, a host E3 ubiquitin (UB) ligase, E6 stirs the protein ubiquitination pathways toward the oncogenic transformation of the infected cells. For a systematic measurement of E6 reprogramming of the substrate pool of E6AP, we performed a proteomic screen based on "orthogonal UB transfer (OUT)" that allowed us to identify the ubiquitination targets of E6AP dependent on the E6 protein of HPV-16, a high-risk viral subtype for the development of cervical cancer. The OUT screen identified more than 200 potential substrates of the E6-E6AP pair based on the transfer of UB from E6AP to the substrate proteins. Among them, we verified that E6 would induce E6AP-catalyzed ubiquitination of importin proteins KPNA1-3, protein phosphatase PGAM5, and arginine methyltransferases CARM1 to trigger their degradation by the proteasome. We further found that E6 could significantly reduce the cellular level of KPNA1 that resulted in the suppression of nuclear transport of phosphorylated STAT1 and the inhibition of interferon-γ-induced apoptosis in cervical cancer cells. Overall, our work demonstrates OUT as a powerful proteomic platform to probe the interaction of E6 and host cells through protein ubiquitination and reveals a new role of E6 in down-regulating nuclear transport proteins to attenuate tumor-suppressive signaling.
Collapse
Affiliation(s)
- Yiyang Wang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Ruochuan Liu
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Jia Liao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Lucen Jiang
- Department of Pathology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Geon H Jeong
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Li Zhou
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Monica Polite
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Duc Duong
- Integrated Proteomics Core, Emory University, Atlanta, Georgia, USA
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Huadong Wang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Hiroaki Kiyokawa
- Department of Pharmacology, Northwestern University, Chicago, Illinois, USA
| | - Jun Yin
- Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| |
Collapse
|
|
36
|
Kono T, Laimins L. Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses. Viruses 2021; 13:1821. [PMID: 34578402 PMCID: PMC8472259 DOI: 10.3390/v13091821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/29/2021] [Accepted: 09/08/2021] [Indexed: 12/22/2022] Open
Abstract
Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.
Collapse
Affiliation(s)
- Takeyuki Kono
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Department of Otolaryngology Head and Neck Surgery, School of Medicine, Keio University, Tokyo 1608582, Japan
| | - Laimonis Laimins
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| |
Collapse
|
|
37
|
Human DLG1 and SCRIB Are Distinctly Regulated Independently of HPV-16 during the Progression of Oropharyngeal Squamous Cell Carcinomas: A Preliminary Analysis. Cancers (Basel) 2021; 13:cancers13174461. [PMID: 34503271 PMCID: PMC8430552 DOI: 10.3390/cancers13174461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary The process of HPV-mediated oncogenesis in HNSCCs is not fully understood. DLG1 and SCRIB protein expression levels and localization changes were evaluated in a number of HPV16-positive and HPV-negative OPSCCs and seem to be associated with malignant transformation. Moreover, loss of SCRIB expression inversely correlates with higher grade tumors, and this is much more evident in the presence of HPV16 E6. This could serve as a potential marker in predicting development of OPSCCs. Abstract The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.
Collapse
|
|
38
|
Women's knowledge and attitude towards cervical cancer preventive measures and associated factors In South Gondar Zone, Amhara Region, North Central Ethiopia: a cross-sectional study. ACTA ACUST UNITED AC 2021; 79:136. [PMID: 34301336 PMCID: PMC8299606 DOI: 10.1186/s13690-021-00659-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 07/14/2021] [Indexed: 12/02/2022]
Abstract
Background Cervical cancer is a leading cause of morbidity and mortality among women in Ethiopia, often due to late disease diagnosis. Early prevention of cancer has been shown to be the most effective measure against the disease. Scientific evidences indicate that lack of awareness towards cervical cancer is a barrier to prevention strategies. Therefore, the aim of the current research was to assess women’s knowledge and attitudes towards cervical cancer preventions in South Gondar zone. Methods A community-based cross-sectional study was carried out in South Gondar zone, Ethiopia. The study sample comprised 844 women ≥ 18 years of age. Participants were selected using systematic sampling technique. Binary and multivariable logistic models were used to assess predictors of women’s knowledge and attitude towards cervical cancer. Results About 66 % of the women had heard about cervical cancer. Regarding the main source of information of respondents, 75.4 % were heard from health professionals. Sixty two point 4 % of women knew at least one preventive measure and 82.6 % of participants knew at least one symptom or sign. Among study participants, 25 and 64 % had good knowledge, and favorable attitude towards cervical cancer prevention measures, respectively. Being reside in rural (AOR = 0.21, 95 %CI; 0.18, 0.34), not attending formal education (AOR = 0.50, 95 % CI: 0.3, 0.75), low income (AOR = 0.57, 95 % CI: 0.43, 0.81) and having < 4 children ((AOR = 0.8, 95 % CI: 0.60–0.86) were negatively associated with knowledge toward cervical cancer prevention measures. Conclusions This study found the majority of the respondents had poor knowledge about cervical cancer prevention measures. The majority of the study participants had favorable attitudes regarding cervical cancer prevention. Living in rural areas, not attending formal education low income and having less than four children was negatively associated with respondents’ knowledge towards cervical cancer prevention measures. There is needed to scale up cervical cancer prevention measures and services .Further studies are needed using strong study design.
Collapse
|
|
39
|
Karube A, Saito F, Waga M, Yokoyama S, Kanamori K. Progression of cervical intraepithelial neoplasia grade 2 lesions among Japanese women harboring different genotype categories of high-risk human papillomaviruses. J Rural Med 2021; 16:91-97. [PMID: 33833834 PMCID: PMC8016672 DOI: 10.2185/jrm.2020-038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/08/2020] [Indexed: 11/27/2022] Open
Abstract
Background: This study aimed to examine whether genotype categories of high-risk human papillomaviruses (HR-HPVs), when divided into HPV16/18, HPV 31/33/45/52/58, and HPV35/39/51/56/59/68, had an effect on the time required for and the proportion of cases that progressed to cervical intraepithelial neoplasia (CIN) grade 3 among women with CIN2. Patients: A total of 160 women aged 20-49 years and having CIN2 were recruited between January 2008 and June 2018. The time required for progression to CIN3 was determined by Kaplan-Meier time-to-event analysis. HPV genotypes were determined using the Linear Array HPV genotyping test. Results: During an average follow-up time of 22 months, 62 (39%) women with CIN2 progressed to CIN3, whereas 34 (21%) eliminated HR-HPVs and became cytologically normal. The majority (63%) of the women harboring HPV16/18 progressed to CIN3 with a 50% progression time of 11 months, whereas 26% of those harboring HPV31/33/45/52/58 progressed to CIN3 with a 50% progression time of 70 months. Conclusion: For every patient diagnosed with CIN2, genotyping to distinguish HPV16/18 from other HR-HPVs should be performed. Therefore, electing a surgical treatment, such as conization, should be considered as the primary option for women who are positive for HPV16/18, particularly when they are likely to be lost for follow-up or are 40 years old or older. In contrast, follow-up cytology should be repeated every 12 months for women harboring non-16/18 HR-HPVs. Those who tested negative for HR-HPV may be followed at the maximum interval of 24 months.
Collapse
Affiliation(s)
- Akihiro Karube
- Department of Obstetrics and Gynecology, Yuri-kumiai General Hospital, Japan
| | - Fumiko Saito
- Department of Obstetrics and Gynecology, Yuri-kumiai General Hospital, Japan
| | - Masato Waga
- Department of Obstetrics and Gynecology, Yuri-kumiai General Hospital, Japan
| | - Shota Yokoyama
- Department of Obstetrics and Gynecology, Yuri-kumiai General Hospital, Japan
| | - Katsuhiro Kanamori
- Department of Obstetrics and Gynecology, Yuri-kumiai General Hospital, Japan
| |
Collapse
|
|
40
|
The safety and efficacy of a novel method for treatment of HSIL. Arch Gynecol Obstet 2021; 304:1291-1298. [PMID: 33813597 DOI: 10.1007/s00404-021-06047-1] [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: 02/21/2020] [Accepted: 03/26/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE To investigate the efficacy and safety of Nr-CWS on treatment of cervical HSIL. METHOD In this observational study, 16 patients were treated with Nr-CWS 1 time every 2 days for 6 times as one-course group (OC group), the other 184 patients were treated with Nr-CWS 1 time every 2 days for 12 times between 2 menstruations as two-course group (TC group). The medical information including age, HPV assay, vaginal-cervical cytology, and the pathological result of biopsy before and after treatment was collected. All patients were followed up at least twice after treatment. The LEEP was performed once the patients with persistent HR-HPV infection and/or abnormal TCT after the second follow-up. RESULTS The cytology remission rate of cervical HSIL in OC and TC group was 100.0% and 87.8%, respectively, which were significant higher than the control (25.0%) with the P value of 2.00 × 10-3 and 2.06 × 10-4. Furthermore, HPV clearance rate was 87.5% and 70.2% in OC and TC group, respectively, which were significant higher than control (32.4%) with the P value of 2.74 × 10-4 and 2.18 × 10-5, respectively. Moreover, the more severe of cytology, the worse effect of HPV clearance for the HPV remission was 75.4%, 68.3%, 67.4%, 65.6% and 64.3% in the negative, LSIL, ASC-US, ASC-H, and HSIL group. 12 patients underwent LEEP after Nr-CWS treatment, 9 (75%) had persistent HSIL and 44.4% cases were found HSIL lesion in the cervical canal. There was no serious adverse reaction observed during treatment and follow-up, four patients were pregnant after treatment and no adverse pregnancy outcomes were observed. CONCLUSION Nr-CWS is an effective and safe drug for treatment of cervical HSIL for Chinese women, especially for cases without lesions in cervical canal.
Collapse
|
|
41
|
Sharmin S, Zohura FT, Islam MS, Shimonty A, Khan MAAK, Parveen R, Sharmin F, Ahsan CR, Islam ABMMK, Yasmin M. Mutational profiles of marker genes of cervical carcinoma in Bangladeshi patients. BMC Cancer 2021; 21:289. [PMID: 33736612 PMCID: PMC7977314 DOI: 10.1186/s12885-021-07906-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 02/12/2021] [Indexed: 01/22/2023] Open
Abstract
Background Cervical cancer is a gynecologic cancer type that develops in the cervix, accounting for 8% mortality of all female cancer patients. Infection with specific human papillomavirus (HPV) types is considered the most severe risk factor for cervical cancer. In the context of our socioeconomic conditions, an increasing burden of this disease and high mortality rate prevail in Bangladesh. Although several researches related to the epidemiology, HPV vaccination, and treatment modalities were conducted, researches on the mutation profiles of marker genes in cervical cancer in Bangladesh remain unexplored. Methods In this study, five different genomic regions within the top three most frequently mutated genes (EGFR, KRAS and PIK3CA) in COSMIC database with a key role in the development of cervical cancers were selected to study the mutation frequency in Bangladeshi patients. In silico analysis was done in two steps: nucleotide sequence analysis and its corresponding amino acid analysis. Results DNA from 46 cervical cancer tissue samples were extracted and amplified by PCR, using 1 set of primers designed for EGFR and 2 sets of primers designed for two different regions of both PIK3CA and KRAS gene. In total, 39 mutations were found in 26 patient samples. Eleven different mutations (23.91%), twenty-four different mutations (52.17%) and four mutations (8.7%) were found in amplified EGFR, PIK3CA and KRAS gene fragments, respectively; among which 1 (EGFR) was common in seven patient samples and 2 (PIKCA) were found in more than 1 patient. Our study shows that except for KRAS, the frequency of observed mutations in our patients is higher than those reported earlier in other parts of the world. Most of the exonic mutations were found only in the PIK3CA and EGFR genes. Conclusions The study can be used as a basis to build a mutation database for cervical cancer in Bangladesh with the possibility of targetable oncogenic mutations. Further explorations are needed to establish future diagnostics, personalized medicine decisions, and other pharmaceutical applications for specific cancer subtypes. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07906-5.
Collapse
Affiliation(s)
- Shahana Sharmin
- Department of Microbiology, University of Dhaka, Dhaka, Bangladesh
| | - Fatima Tuj Zohura
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.,Current Affiliation: Internal Medicine OPD, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka, Bangladesh
| | - Md Sajedul Islam
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.,Current Affiliation: Department of Biochemistry and Biotechnology, University of Barisal, Barisal, Bangladesh
| | - Anika Shimonty
- Department of Microbiology, University of Dhaka, Dhaka, Bangladesh
| | - Md Abdullah-Al-Kamran Khan
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.,Current Affiliation Department of Mathematics and Natural Sciences, BRAC University, Dhaka, Bangladesh
| | | | - Foujia Sharmin
- Department of Gynecological Oncology, National Institute of Cancer Research & Hospital, Dhaka, Bangladesh
| | | | | | - Mahmuda Yasmin
- Department of Microbiology, University of Dhaka, Dhaka, Bangladesh.
| |
Collapse
|
|
42
|
Tu TY, Chang R, Lai JN, Tseng CC, Chen ML, Yip HT, Hung YM, Cheng-Chung Wei J. Human papillomavirus symptomatic infection associated with increased risk of new-onset alopecia areata: A nationwide population-based cohort study. J Autoimmun 2021; 119:102618. [PMID: 33714796 DOI: 10.1016/j.jaut.2021.102618] [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: 11/17/2020] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND We investigated the correlation between a history of human papillomavirus (HPV) infection and alopecia areata risk. METHODS The study cohort comprised 30,001 patients with newly diagnosed HPV infection between 2000 and 2012; and with use of computer-generated randomly numbers, patients not had HPV infection were randomly selected as the comparison cohort. HPV infection cohort were matched to comparison individuals at a 1:1 ratio by age, gender and index year. All study individuals were followed up until they developed alopecia areata, withdraw from the insurance program, lost to follow-up, or until the end of 2013. Cox proportional hazards regression analysis was used to analyze the risk of alopecia areata with hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. RESULTS The adjusted hazard ratio (aHR) of alopecia areata for HPV patients relative to controls was 2.55 (95% C.I. = 1.88-3.47) after adjusting sex, age and comorbidities. Subgroup analysis indicated that patients with HPV infections had a significantly greater risk of alopecia areata for both genders, all age subgroups, and those with mental disorder diseases. CONCLUSIONS A history of HPV infection is associated with the development of subsequent alopecia areata in Taiwanese subjects.
Collapse
Affiliation(s)
- Ting-Yu Tu
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Renin Chang
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Jung-Nien Lai
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chu-Chiao Tseng
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Li Chen
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hei-Tung Yip
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; Institute of Public Health, National Yangming University, Taiwan
| | - Yao-Min Hung
- Department of Internal Medicine, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; College of Health and Nursing, Meiho University, Pingtung, Taiwan; Tajen University, Pingtung, Taiwan.
| | - James Cheng-Chung Wei
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; Division of Allergy, Immunology and Rheumatology, Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| |
Collapse
|
|
43
|
Fan Q, Huang T, Sun X, Wang YW, Wang J, Liu Y, Ni T, Gu SL, Li YH, Wang YD. HPV-16/18 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Mol Carcinog 2021; 60:313-330. [PMID: 33631046 DOI: 10.1002/mc.23292] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 12/13/2022]
Abstract
Oncogenic high-risk human papillomavirus (HR-HPV) infection causes a majority of cases of cervical cancer and pre-cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV-16/18-infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA-seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV-16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV-16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA-mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl-capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV-16 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.
Collapse
Affiliation(s)
- Qiong Fan
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Municipal Key Clinical Specialty, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Ting Huang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Municipal Key Clinical Specialty, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Xiao Sun
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Municipal Key Clinical Specialty, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Yi-Wei Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yao Liu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Ni
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Sheng-Lan Gu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Hong Li
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Dong Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Municipal Key Clinical Specialty, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| |
Collapse
|
|
44
|
Park S, Auyeung A, Lee DL, Lambert PF, Carchman EH, Sherer NM. HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins. Cancers (Basel) 2021; 13:949. [PMID: 33668328 PMCID: PMC7956332 DOI: 10.3390/cancers13050949] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/09/2021] [Accepted: 02/20/2021] [Indexed: 02/05/2023] Open
Abstract
High-risk human papillomavirus strain 16 (HPV16) causes oral and anogenital cancers through the activities of two viral oncoproteins, E6 and E7, that dysregulate the host p53 and pRb tumor suppressor pathways, respectively. The maintenance of HPV16-positive cancers requires constitutive expression of E6 and E7. Therefore, inactivating these proteins could provide the basis for an anticancer therapy. Herein we demonstrate that a subset of aspartyl protease inhibitor drugs currently used to treat HIV/AIDS cause marked reductions in HPV16 E6 and E7 protein levels using two independent cell culture models: HPV16-transformed CaSki cervical cancer cells and NIKS16 organotypic raft cultures (a 3-D HPV16-positive model of epithelial pre-cancer). Treatment of CaSki cells with some (lopinavir, ritonavir, nelfinavir, and saquinavir) but not other (indinavir and atazanavir) protease inhibitors reduced E6 and E7 protein levels, correlating with increased p53 protein levels and decreased cell viability. Long-term (>7 day) treatment of HPV16-positive NIKS16 raft cultures with saquinavir caused epithelial atrophy with no discernible effects on HPV-negative rafts, demonstrating selectivity. Saquinavir also reduced HPV16's effects on markers of the cellular autophagy pathway in NIKS16 rafts, a hallmark of HPV-driven pre-cancers. Taken together, these data suggest HIV-1 protease inhibitors be studied further in the context of treating or preventing HPV16-positive cancers.
Collapse
Affiliation(s)
- Soyeong Park
- McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.P.); (D.L.L.); (P.F.L.)
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
| | - Andrew Auyeung
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
| | - Denis L. Lee
- McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.P.); (D.L.L.); (P.F.L.)
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.P.); (D.L.L.); (P.F.L.)
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
| | - Evie H. Carchman
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
| | - Nathan M. Sherer
- McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.P.); (D.L.L.); (P.F.L.)
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (A.A.); (E.H.C.)
| |
Collapse
|
|
45
|
Zhang C, Fu S, Wang L, Wang F, Wu D, Zhe X, Xin H, Li H, Li D, Jin F, Shao R, Pan Z. The Value and Clinical Significance of ZNF582 Gene Methylation in the Diagnosis of Cervical Cancer. Onco Targets Ther 2021; 14:403-411. [PMID: 33488095 PMCID: PMC7814240 DOI: 10.2147/ott.s277445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 11/18/2020] [Indexed: 11/23/2022] Open
Abstract
Introduction The aim of this study was to determine whether ZNF582 gene methylation and tissue protein expression can be used as a tool with high sensitivity and specificity for cervical cancer screening. We analyzed the correlation between promoter methylation of ZNF582 gene and cervical cancer and high risk HPV16/18 infection. Methods Tissue samples of normal cervical or chronic cervicitis (n=51), CIN (cervical intraepithelial neoplasia) (n=35), and cervical carcinoma (n=68) were tested for HPV16/18 infection by polymerase chain reaction (PCR). We also detected the methylation status of the ZNF582 gene promoter in the same tissues by methylation-specific PCR (MSP), then analyzed the correlation between ZNF582 promoter methylation and HPV16/18 infection. Immunohistochemistry was used to analyze ZNF582 gene expression in 152 cervical tissues. We detected ZNF582 mRNA expression in cervical tissues (including cancer and non-cancer) by real-time fluorescence quantitative PCR (qPCR). Results Among 93 high-grade cervical lesions (CINII and above) and cervical cancer samples, 57 cases were positive for HPV16/18 infection and 36 cases were negative. ZNF582 gene methylation occurred in 9 out of 51 cases in normal cervical tissues (17.6%), 16 of 35 cases in CIN tissues (45.7%), and 50 of 68 cases in cervical cancer (73.5%). The differences in methylation rate of the three groups were statistically significant (P<0.05). The ZNF582 methylation rate in the positive HPV16/18 infection group was 73.7%, while the negative group was 63.9%. Compared with normal tissues, ZNF582 protein was highly expressed in cervical cancer tissues, but mRNA expression was low. Conclusion While ZNF582 protein is highly expressed in cervical cancer tissues, it was not sufficient for use as a standard for cervical cancer staging. On the other hand, ZNF582 promoter methylation had high specificity and sensitivity in detecting CINII and highly diseased cervical lesions and could be used as a diagnostic marker for cervical cancer of women.
Collapse
Affiliation(s)
- Chunhe Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Shaowei Fu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Luyue Wang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Fang Wang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Dan Wu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Xiangyi Zhe
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Huizhen Xin
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Hongtao Li
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Dongmei Li
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Fuyuan Jin
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| | - Renfu Shao
- School of Science, Technology and Engineering, Genecology Research Centre, University of the Sunshine Coast, Sippy Downs, Queensland 4556, Australia
| | - Zemin Pan
- Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang 832002, People's Republic of China
| |
Collapse
|
|
46
|
Kumagai K, Takanashi M, Ohno SI, Harada Y, Fujita K, Oikawa K, Sudo K, Ikeda SI, Nishi H, Oikawa K, Kuroda M. WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7. Oncogene 2021; 40:3695-3706. [PMID: 33947962 PMCID: PMC8154587 DOI: 10.1038/s41388-021-01787-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 02/03/2023]
Abstract
Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.
Collapse
Affiliation(s)
- Katsuyoshi Kumagai
- grid.410793.80000 0001 0663 3325Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan
| | - Masakatsu Takanashi
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Shin-ichiro Ohno
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yuichirou Harada
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Koji Fujita
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Keiki Oikawa
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Katsuko Sudo
- grid.410793.80000 0001 0663 3325Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan
| | - Shun-ichi Ikeda
- Department of Obstetrics and Gynecology, Kohseichuo General Hospital, Tokyo, Japan
| | - Hirotaka Nishi
- grid.410793.80000 0001 0663 3325Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Kosuke Oikawa
- grid.412857.d0000 0004 1763 1087Department of Pathology, Wakayama Medical University, Wakayama, Japan
| | - Masahiko Kuroda
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| |
Collapse
|
|
47
|
Chakraborty B, Mukhopadhyay D, Roychowdhury A, Basu M, Alam N, Chatterjee K, Chakrabarti J, Panda CK. Differential Wnt-β- catenin pathway activation in HPV positive and negative oral epithelium is transmitted during head and neck tumorigenesis: clinical implications. Med Microbiol Immunol 2020; 210:49-63. [PMID: 33226516 DOI: 10.1007/s00430-020-00697-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022]
Abstract
The aim of this study is to understand the association of HPV infection and wnt-β-catenin self-renewal pathway in development of head and neck squamous cell carcinoma (HNSCC). For this reason, the molecular profiles (methylation/deletion/expression) of antagonists (SFRP1/2 and DKK1), agonists (FZD7 and LRP6) and effector protein β-catenin of the pathway were analyzed in HPV positive/negative oral epithelium at first, followed by its changes during development of the tumor along with correlations with different clinico-pathological parameters. HPV infection alone or in combination with tobacco habit could activate p- β-catenin expression in basal/parabasal layers of oral epithelium through high expression of FZD7 and significant down regulation of SFRP1/2 through promoter hypermethylation due to over expression of DNMT1 with ubiquitous down regulation of DKK1 and up-regulation of LRP6. This phenomenon has been seen in respective HPV positive and negative HNSCC tumors with additional deletion/microsatellite size alterations in the antagonists. Overall alterations (methylation/deletion) of SFRP1/2, DKK1 gradually increased from Group I (HPV-/Tobacco-) to Group IV(HPV+/Tobacco+) tumors, leading to the worst prognosis of the patients. Thus, the transmission of differentially activated wnt-β-catenin pathway from HPV positive/negative basal/parabasal layers of oral epithelium to HNSCC tumors determines differences in molecular pathogenesis of the disease.
Collapse
Affiliation(s)
- Balarko Chakraborty
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Debalina Mukhopadhyay
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Anirban Roychowdhury
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Mukta Basu
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Neyaz Alam
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Kabita Chatterjee
- Consultant Oral and Maxillofacial Pathologist. 3, Raja Manindra Road, Kolkata, West Bengal, 700037, India
| | - Jayanta Chakrabarti
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India.
| |
Collapse
|
|
48
|
Rho SB, Lee SH, Byun HJ, Kim BR, Lee CH. IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer. Int J Mol Sci 2020; 21:ijms21207622. [PMID: 33076322 PMCID: PMC7589982 DOI: 10.3390/ijms21207622] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022] Open
Abstract
HPV16 E6 oncoprotein is a member of the human papillomavirus (HPV) family that contributes to enhanced cellular proliferation and risk of cervical cancer progression via viral infection. In this study, interferon regulatory factor-1 (IRF-1) regulates cell growth inhibition and transcription factors in immune response, and acts as an HPV16 E6-binding cellular molecule. Over-expression of HPV16 E6 elevated cell growth by attenuating IRF-1-induced apoptosis and repressing p21 and p53 expression, but activating cyclin D1 and nuclear factor kappa B (NF-κB) expression. The promoter activities of p21 and p53 were suppressed, whereas NF-κB activities were increased by HPV16 E6. Additionally, the cell viability of HPV16 E6 was diminished by IRF-1 in a dose-dependent manner. We found that HPV16 E6 activated vascular endothelial growth factor (VEGF)-induced endothelial cell migration and proliferation as well as phosphorylation of VEGFR-2 via direct interaction in vitro. HPV16 E6 exhibited potent pro-angiogenic activity and clearly enhanced the levels of hypoxia-inducible factor-1α (HIF-1α). By contrast, the loss of function of HPV16 E6 by siRNA-mediated knockdown inhibited the cellular events. These data provide direct evidence that HPV16 E6 facilitates tumour growth and angiogenesis. HPV16 E6 also activates the PI3K/mTOR signalling cascades, and IRF-1 suppresses HPV16 E6-induced tumourigenesis and angiogenesis. Collectively, these findings suggest a biological mechanism underlying the HPV16 E6-related activity in cervical tumourigenesis.
Collapse
Affiliation(s)
- Seung Bae Rho
- Division of Translational Science, Research Institute, National Cancer Center, Goyang, Gyeonggido 411-769, Korea;
| | - Seung-Hoon Lee
- Department of Life Science, Yong In University, Yongin, Gyeonggido 449-714, Korea;
| | - Hyun-Jung Byun
- Phamaceutical Biochemistry, College of Pharmacy and Integrated Research Institute for Drug, Dongguk University, Goyang 100-715, Korea;
| | - Boh-Ram Kim
- Phamaceutical Biochemistry, College of Pharmacy and Integrated Research Institute for Drug, Dongguk University, Goyang 100-715, Korea;
- Correspondence: (B.-R.K.); (C.H.L.); Tel.: +82-31-961-5213 (B.-R.K. & C.H.L.)
| | - Chang Hoon Lee
- Phamaceutical Biochemistry, College of Pharmacy and Integrated Research Institute for Drug, Dongguk University, Goyang 100-715, Korea;
- Correspondence: (B.-R.K.); (C.H.L.); Tel.: +82-31-961-5213 (B.-R.K. & C.H.L.)
| |
Collapse
|
|
49
|
Revathidevi S, Murugan AK, Nakaoka H, Inoue I, Munirajan AK. APOBEC: A molecular driver in cervical cancer pathogenesis. Cancer Lett 2020; 496:104-116. [PMID: 33038491 PMCID: PMC7539941 DOI: 10.1016/j.canlet.2020.10.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/16/2020] [Accepted: 10/04/2020] [Indexed: 02/09/2023]
Abstract
Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.
APOBEC enzymes deaminate cytidine to uridine and control diverse biological processes including viral restriction. APOBEC3, DNA/RNA-editing enzyme plays an important role in the molecular pathogenesis of cervical cancer. APOBEC3-mediated DNA editing leads to the accumulation of somatic mutations in tumors and HPV genome. Deregulation of APOBEC3 family genes cause genomic instability and result in drug resistance, and immune-evasion in tumors.
Collapse
Affiliation(s)
- Sundaramoorthy Revathidevi
- Department of Genetics, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai, 600113, India; Division of Human Genetics, National Institute of Genetics, Mishima, 411-8540, Japan
| | - Avaniyapuram Kannan Murugan
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Hirofumi Nakaoka
- Division of Human Genetics, National Institute of Genetics, Mishima, 411-8540, Japan; Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Chiyoda-ku, 101-0062, Japan
| | - Ituro Inoue
- Division of Human Genetics, National Institute of Genetics, Mishima, 411-8540, Japan
| | - Arasambattu Kannan Munirajan
- Department of Genetics, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai, 600113, India.
| |
Collapse
|
|
50
|
Park YC, Ouh YT, Sung MH, Park HG, Kim TJ, Cho CH, Park JS, Lee JK. A phase 1/2a, dose-escalation, safety and preliminary efficacy study of oral therapeutic vaccine in subjects with cervical intraepithelial neoplasia 3. J Gynecol Oncol 2020; 30:e88. [PMID: 31576684 PMCID: PMC6779607 DOI: 10.3802/jgo.2019.30.e88] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 03/27/2019] [Accepted: 04/18/2019] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Persistent infection of HPV increases the chance of carcinoma in situ of cervix through stages of cervical intraepithelial neoplasia (CIN) 1, 2, and 3, and finally progresses into cervical cancer. We aimed to explore the safety and efficacy of BLS-M07 which is orally administered agent expressing human papillomavirus (HPV) 16 E7 antigen on the surface of Lactobacillus casei in patients with CIN 3. METHODS Patients with CIN 3 were recruited in our clinical trial. Reid Colposcopic Index (RCI) grading and serum HPV16 E7 specific antibody production were used to evaluate efficacy of BLS-M07. In phase 1, BLS-M07 was administered orally, 5 times a week, on weeks 1, 2, 4, and 8 with dosages of 500 mg, 1,000 mg, and 1,500 mg. In phase 2a, patients were treated with 1,000 mg. The primary endpoints were the safety and the pathologic regression on colposcopic biopsy. RESULTS Nineteen patients were enrolled in the CIN 3 cohort. In phase 1, no patients experienced dose limiting toxicity. No grade 3 or 4 treatment-related adverse events or deaths were observed. At 16 weeks after treatment, RCI grading was improved and serum HPV16 E7 specific antibody production increased (p<0.05). Six of 8 (75%) patients with CIN 3 were cured in phase 2a. CONCLUSIONS Oral immunization with BLS-M07 increases production of serum HPV16 E7 specific antibody which induces protective humoral immunity. The safety of this oral vaccine was proved and could be a competitive non-surgical therapeutic agent of CIN 3. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02195089.
Collapse
Affiliation(s)
| | - Yung Taek Ouh
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, College of Medicine, Korea University, Seoul, Korea
| | - Moon Hee Sung
- BioLeaders Corporation, Yongin, Korea.,Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, Korea
| | | | - Tae Jin Kim
- General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea
| | - Chi Heum Cho
- Department of Obstetrics and Gynecology, Keimyung University, School of Medicine, Daegu, Korea
| | - Jong Sup Park
- Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Jae Kwan Lee
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, College of Medicine, Korea University, Seoul, Korea.
| |
Collapse
|