Degradation of p53 by HPV16-E6 variants isolated from cervical cancer specimens of Moroccan women

Abstract Background Human papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China. Methods We aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher’s exact test. Results In this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1–3 (European) sublineages (OR = 2.69, 95% CI = 1.04–6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer. Conclusion These data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China.

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miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer

10.21203/rs.2.9472/v1 ◽

2019 ◽

Author(s):

Hui Wang ◽

Hui Hu ◽

Zhenzhao Luo ◽

Shuiyi Liu ◽

Wangze Wu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Invasion ◽

Tumor Suppressor Genes ◽

Target Gene ◽

Migration And Invasion ◽

Caski Cell ◽

Hpv16 E6 ◽

Invasion And Migration ◽

C33a Cell ◽

And Migration

Abstract The abnormal expression of HPV16 E6/E7 activates oncogenes and/or inactivates tumor suppressor genes, resulting in the selective growth and malignant transformation of cancer cells. miR-4454 was selected by sequencing due to its abnormal high expression in HPV16 E6/E7 positive CaSki cell compared with HPV16 E6/E7 negative C33A cell. Overexpression of miR-4454 enhances cervical cancer cell invasion and migration. ABHD2 and NUDT21 is identified as a target gene of miR-4454.The effects of ABHD2 and NUDT21 on migration and invasion of CaSki and C33A cells were determined. The dual luciferase and RT-qPCR assays confirmed that miR-4454 might regulate its targets ABHD2 and NUDT21 to promote the proliferation, invasion and migration, whereas, inhibit the apoptosis in CaSki and C33A cells.

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HPV16 E6 oncoprotein‐induced upregulation of lncRNA GABPB1‐AS1 facilitates cervical cancer progression by regulating miR‐519e‐5p/Notch2 axis

The FASEB Journal ◽

10.1096/fj.202000762r ◽

2020 ◽

Vol 34 (10) ◽

pp. 13211-13223

Author(s):

Rongying Ou ◽

Mingfen Lv ◽

Xuan Liu ◽

Jiangmin Lv ◽

Jinduo Zhao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Hpv16 E6 ◽

E6 Oncoprotein

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Reasons for cervical cancer screening participation among Turkish- and Moroccan-Dutch: focus groups

European Journal of Public Health ◽

10.1093/eurpub/ckz186.375 ◽

2019 ◽

Vol 29 (Supplement_4) ◽

Author(s):

E Marchena ◽

N Hamdiui ◽

M L Stein ◽

J E van Steenbergen ◽

M van den Muijsenbergh ◽

...

Keyword(s):

Cervical Cancer ◽

Focus Groups ◽

Health Belief ◽

Participation Rate ◽

Barriers And Facilitators ◽

Screening Participation ◽

Dutch Language ◽

Moroccan Women ◽

Information Materials ◽

Belief Model

Abstract Background Cervical cancer (CC) is ranked fourth most frequently diagnosed cancer in women worldwide. Compared to the 79% CC screening participation rate of native Dutch women, the rate of 64% among Turkish- and 53% among Moroccan-Dutch women is considerably lower. Our aim was to explore reasons for CC screening (non)participation of Turkish- and Moroccan-Dutch women, and their attitude towards self-sampling. Methods Six focus groups were conducted in March and April 2019 with Turkish (n = 25) and Moroccan (n = 20) women in the Netherlands, aged 30-60 years. Questions were based on an extended Health Belief Model. Discussions were transcribed verbatim and thematically analysed. Results We found that women lack knowledge and awareness about CC. Barriers for screening were lack of a good command of the Dutch language, having a male as general practitioner, fatalism, shame and taboo related to the intimate procedure, and the association of CC with lack of femininity and infertility. Other barriers were fears of the test result, cancer, suffering, death, and leaving their children behind after death. Facilitators were perceived severity of disease, social support, and short procedure time. Additional religious facilitators included the responsibility to take care of one’s own health using medical facilities that God provided. Differences were found between Turkish and Moroccan women, such as lack of a good command of the Dutch language. Conflicting attitudes were found regarding self-sampling. Although perceived easy and accessible, women were hesitant whether they could sample correctly. Overall, women preferred a physician-taken smear to a self-sample. Conclusions Several barriers and facilitators for CC screening participation were identified that can be used to design tailored information materials. Women’s doubts about incorrect self-sampling should be taken into account to encourage self-sampling among nonparticipating Turkish and Moroccan women. Key messages Important barriers and facilitators were identified that can be used to well-inform Turkish and Moroccan women. To promote self-sampling, women’s attitudes on their self-efficacy should be explored.

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High expression of CCDC106 promotes cervical cancer cell proliferation and migration by p53 degradation despite the HPV16 E6 spliced status

Gynecologic Oncology ◽

10.1016/j.ygyno.2020.05.289 ◽

2020 ◽

Vol 159 ◽

pp. 188

Author(s):

C. Cao ◽

W. Zhi ◽

S. Lin ◽

P. Wu

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

High Expression ◽

Cervical Cancer Cell ◽

Cancer Cell Proliferation ◽

Hpv16 E6 ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

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Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses

Science Translational Medicine ◽

10.1126/scitranslmed.aad8307 ◽

2016 ◽

Vol 8 (334) ◽

pp. 334ra52-334ra52 ◽

Cited By ~ 89

Author(s):

Marij J. Welters ◽

Tetje C. van der Sluis ◽

Hélène van Meir ◽

Nikki M. Loof ◽

Vanessa J. van Ham ◽

...

Keyword(s):

Cervical Cancer ◽

T Cell ◽

Myeloid Cells ◽

Myeloid Cell ◽

T Cell Responses ◽

Mouse Tumor ◽

Therapeutic Vaccination ◽

Advanced Cervical Cancer ◽

Hpv16 E6 ◽

Cell Responses

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7–positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1–bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.

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Analysis of mutations in the E6/E7 oncogenes and L1 gene of human papillomavirus 16 cervical cancer isolates from China

Journal of General Virology ◽

10.1099/vir.0.81649-0 ◽

2006 ◽

Vol 87 (5) ◽

pp. 1181-1188 ◽

Cited By ~ 30

Author(s):

Yuping Wu ◽

Yulong Chen ◽

Longyu Li ◽

Guifang Yu ◽

Ying He ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Patients ◽

Hpv Infection ◽

Typing Method ◽

Hpv16 E6 ◽

Human Papillomavirus 16 ◽

Human Papillomavirus Type 16 ◽

New Variant

Human papillomavirus type 16 (HPV16) has a number of intratypic variants; each has a different geographical distribution and some are associated with enhanced oncogenic potential. Cervical samples were collected from 223 cervical cancer patients and from 196 age-matched control subjects in China. DNA samples were amplified by using primers specific for the E6, E7 and partial L1 regions. Products were sequenced and analysed. It was found by using a PCR–sequence-based typing method that HPV infection rates in China were 92·8 % in cervical cancer patients and 15·8 % in healthy controls. HPV16 was detected in 70·4 % of cervical cancer patients and in 6·1 % of controls. In HPV16-positive cervical cancers, 23·6 % belonged to the prototype, 65·5 % were of the Asian variant, 5·5 % were of African type 1 and 3·6 % were European variants, whilst only one was a new variant that differed from any variant published so far. Prevalences of HPV16 E6 D25E and E113D variants were 67·3 and 9 %, respectively. In addition to D25E and E113D, the following E6 variations were found in this study: R129K, E89Q, S138C, H78Y, L83V and F69L. The results also showed that the prevalences of three hot spots of E7 nucleotide variation, N29S, S63F and a silent variation, nt T846C, were 70·2 % (33/47), 51·1 % (24/47) and 61·7 % (29/47), respectively. The following L1 variations were found in this study: S377A, K387E, E378D, K382E and T379P. It was also found that the average age of Asian variant-positive cervical cancer patients (42·98±10·43 years) was 7·56 years lower than that of prototype-positive patients (50·54±10·91). It is suggested that the high frequency of HPV16 Asian variants might contribute to the high incidence of cervical cancer in China.

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ICAT Promotes Cervical Cancer Cell Proliferation, Invasion, Migration and Epithelial‑to‑mesenchymal Transition Through HPV16 E6, E7/ miR-23b-3p/ ICAT Axis

10.21203/rs.3.rs-101315/v2 ◽

2021 ◽

Author(s):

Jing Hu ◽

Zijiu Sun ◽

Hui Wang ◽

Wei Ren ◽

Yuting Fang ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Recombinant Adenovirus ◽

Cervical Cancer Cell ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Hpv 16 ◽

Hpv16 E6 ◽

Mesenchymal Transition

Abstract Background: Human papillomavirus (HPV) 16 plays a crucial role in cervical cancer (CC) development. Previous study reported that inhibitor of β-catenin and TCF (ICAT) is upregulated in CC and promotes cervical tumor progression. Herein, we aimed to investigate the underlying molecular mechanism that HPV16 regulates the expression of ICAT and promotes the CC development. Methods: The expressions of HPV 16 E6, E7 and ICAT were modulated by small interfering RNA and recombinant adenovirus, respectively. qRT-PCR was conducted to detect the mRNA expression of HPV 16 E6, E7, ICAT and miR-23b-3p in SiHa and CasKi cells. Bioinformatics analysis was utilized to predict the potential miRNAs that could bind to the ICAT 3′ untranslated region. Then, the dual luciferase reporter assay was used to confirm that. Cell proliferation ability was detected by CCK-8 assay. Wound healing and Transwell assays were used to observe migration and invasion abilities. Protein expressions were measured with western blot. Results: Results revealed that after knocking down of HPV16 E6, E7, the expression of ICAT decreased, but the expression of miR-23b-3p increased. Besides, miR-23b-3p negatively modulated ICAT expression in HPV16 positive CC cells. Dual luciferase assays confirmed that ICAT was a target gene of miR-23b-3p. Functional experiments showed that the overexpression of miR-23b-3p suppressed malignant behaviors of SiHa and CasKi cells, such as migration, invasion and EMT. Importantly, the overexpression of ICAT counteracted the suppressive effect of miR-23b-3p on HPV16 positive cervical cancer cell. Furthermore, after the knockdown of HPV16 E6 and E7, the inhibition of miR-23b-3p could increase the ICAT expression and rescue the siRNA HPV16 E6, E7-mediated suppressive impact on the aggressiveness of SiHa and CasKi cells.Conclusions: Our study demonstrates that HPV 16 E6, E7/miR-23b-3p/ ICAT axis plays an important role in HPV16 positive CC pathogenesis, which may serve as a promising therapy target for HPV 16-associated cervical cancer.

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HPV16 E6-178G/E7-647G Promotes Proliferation and Inhibits Apoptosis in Cervical Cancer C33A Cells

10.21203/rs.3.rs-153936/v2 ◽

2021 ◽

Author(s):

Xiangyi Zhe ◽

Huizhen Xin ◽

Chunhe Zhang ◽

Zhenzhen Pan ◽

Dongmei Li ◽

...

Keyword(s):

Cervical Cancer ◽

Flow Cytometry ◽

Cell Proliferation ◽

Cell Cloning ◽

Proliferation Assay ◽

Hpv16 E6 ◽

Proliferation And Apoptosis ◽

Cervical Cancer Cells ◽

Cloning Assay

Abstract Background：HPV16 is the main cause of cervical cancer. In our study, we aimed to investigate the role of HPV mutants HPV16 E6-178G/E7-647G in the proliferation and apoptosis of cervical cancer C33A cells. Methods：Plasmids encoding the HPV16 E7 prototype (E7-647A)-GV144, E7 mutant (E7-647G)-GV144, HPV16 E6/E7 prototype (E6-178T/E7-647A)-GV144, and E6/E7 mutant (E6-178G/E7-647G)-GV144 were stably transfected into cervical cancer C33A cells. Western blot analysis, CCK8 proliferation assay, cell cloning assay and flow cytometry were used to detect the effects of the different polymorphism sites in HPV16 on cell proliferation and apoptosis. Results：HPV16 mutations promoted the proliferation and inhibited the apoptosis of cervical cancer C33A cells, and the effect of the E6-178G/E7-647G co-mutation was significantly greater than that of the single E7-647G mutant (P<0.05). Conclusions：HPV16 E6-178G/E7-647G can thus promote the proliferation and inhibit the apoptosis of cervical cancer cells.

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