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Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells

Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key vi...

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Autores principales: Zhu, Jinshun, Kamara, Saidu, Wang, Qi, Guo, Yanru, Li, Qingfeng, Wang, Linlin, Chen, Jingjing, Du, Qianqian, Du, Wangqi, Chen, Shao, Zhu, Shanli, Chen, Jun, Chu, Maoping, Zhang, Lifang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181454/
https://www.ncbi.nlm.nih.gov/pubmed/34109181
http://dx.doi.org/10.3389/fcell.2021.677867
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author Zhu, Jinshun
Kamara, Saidu
Wang, Qi
Guo, Yanru
Li, Qingfeng
Wang, Linlin
Chen, Jingjing
Du, Qianqian
Du, Wangqi
Chen, Shao
Zhu, Shanli
Chen, Jun
Chu, Maoping
Zhang, Lifang
author_facet Zhu, Jinshun
Kamara, Saidu
Wang, Qi
Guo, Yanru
Li, Qingfeng
Wang, Linlin
Chen, Jingjing
Du, Qianqian
Du, Wangqi
Chen, Shao
Zhu, Shanli
Chen, Jun
Chu, Maoping
Zhang, Lifang
author_sort Zhu, Jinshun
collection PubMed
description Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (Z(HPV16E6)1115, Z(HPV16E6)1171, and Z(HPV16E6)1235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo. Moreover, by binding to HPV16 E6 protein, Z(HPV16E6)1235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, Z(HPV16E6)1235 was applied in combination with HPV16 E7-binding affibody Z(HPV16E7)384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions.
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spelling pubmed-81814542021-06-08 Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells Zhu, Jinshun Kamara, Saidu Wang, Qi Guo, Yanru Li, Qingfeng Wang, Linlin Chen, Jingjing Du, Qianqian Du, Wangqi Chen, Shao Zhu, Shanli Chen, Jun Chu, Maoping Zhang, Lifang Front Cell Dev Biol Cell and Developmental Biology Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (Z(HPV16E6)1115, Z(HPV16E6)1171, and Z(HPV16E6)1235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo. Moreover, by binding to HPV16 E6 protein, Z(HPV16E6)1235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, Z(HPV16E6)1235 was applied in combination with HPV16 E7-binding affibody Z(HPV16E7)384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions. Frontiers Media S.A. 2021-05-24 /pmc/articles/PMC8181454/ /pubmed/34109181 http://dx.doi.org/10.3389/fcell.2021.677867 Text en Copyright © 2021 Zhu, Kamara, Wang, Guo, Li, Wang, Chen, Du, Du, Chen, Zhu, Chen, Chu and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Zhu, Jinshun
Kamara, Saidu
Wang, Qi
Guo, Yanru
Li, Qingfeng
Wang, Linlin
Chen, Jingjing
Du, Qianqian
Du, Wangqi
Chen, Shao
Zhu, Shanli
Chen, Jun
Chu, Maoping
Zhang, Lifang
Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title_full Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title_fullStr Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title_full_unstemmed Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title_short Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells
title_sort novel affibody molecules targeting the hpv16 e6 oncoprotein inhibited the proliferation of cervical cancer cells
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181454/
https://www.ncbi.nlm.nih.gov/pubmed/34109181
http://dx.doi.org/10.3389/fcell.2021.677867
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