Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells
High-risk human papillomavirus (HPV) types 16 and 18 are associated with more than 70% of cervical cancer cases. The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2015-10, Vol.465 (4), p.658-664 |
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| creator | Bonetta, Anaëlle Charlotte Mailly, Laurent Robinet, Eric Travé, Gilles Masson, Murielle Deryckere, François |
| description | High-risk human papillomavirus (HPV) types 16 and 18 are associated with more than 70% of cervical cancer cases. The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for degradation by the 26S proteasome. Loss of p53 triggers genomic instability and favors cancer development. Here, we generated recombinant adenovirus (Ad) vectors expressing artificial microRNAs directed against HPV16 E6 (Ad16_1) or HPV18 E6 (Ad18_2). E6-knockdown was observed in HeLa after treatment with Ad18_2 and in SiHa with Ad16_1. Western-blot experiments found an increase in p53 levels after treatment in both cell lines. Cell death was observed in both cell lines after knockdown of E6. Further analysis such as cleavage of caspases (3 and 7) as well as of PARP1 indicated that treated HeLa and SiHa cells underwent apoptosis. The growth of HeLa-derived tumors developed in nude mice was significantly reduced after intra-tumoral injection of Ad18_2. Therefore, vectorisation of artificial miRNA against E6 oncoprotein by means of recombinant adenoviruses might represent a valuable therapeutic approach for treating HPV-positive cancers. |
| doi_str_mv | 10.1016/j.bbrc.2015.07.144 |
| format | Article |
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The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for degradation by the 26S proteasome. Loss of p53 triggers genomic instability and favors cancer development. Here, we generated recombinant adenovirus (Ad) vectors expressing artificial microRNAs directed against HPV16 E6 (Ad16_1) or HPV18 E6 (Ad18_2). E6-knockdown was observed in HeLa after treatment with Ad18_2 and in SiHa with Ad16_1. Western-blot experiments found an increase in p53 levels after treatment in both cell lines. Cell death was observed in both cell lines after knockdown of E6. Further analysis such as cleavage of caspases (3 and 7) as well as of PARP1 indicated that treated HeLa and SiHa cells underwent apoptosis. The growth of HeLa-derived tumors developed in nude mice was significantly reduced after intra-tumoral injection of Ad18_2. Therefore, vectorisation of artificial miRNA against E6 oncoprotein by means of recombinant adenoviruses might represent a valuable therapeutic approach for treating HPV-positive cancers.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2015.07.144</identifier><identifier>PMID: 26241675</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenoviridae - genetics ; Adenovirus ; Animals ; Apoptosis - genetics ; Cancer therapy ; Cell Line ; Cervical cancer ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - genetics ; Female ; Gene Knockdown Techniques ; Gene therapy ; Genetic Therapy ; Genetic Vectors ; HeLa Cells ; Human health and pathology ; Human papillomavirus ; Human papillomavirus 16 ; Human papillomavirus 16 - genetics ; Human papillomavirus 16 - pathogenicity ; Human papillomavirus 18 ; Human papillomavirus 18 - genetics ; Human papillomavirus 18 - pathogenicity ; Humans ; Life Sciences ; Mice ; Mice, Nude ; MicroRNAs - genetics ; Oncogene Proteins, Viral - antagonists & inhibitors ; Oncogene Proteins, Viral - genetics ; Papillomavirus Infections - pathology ; Papillomavirus Infections - therapy ; Papillomavirus Infections - virology ; Repressor Proteins - antagonists & inhibitors ; Repressor Proteins - genetics ; RNA interference ; Tumor Suppressor Protein p53 - metabolism ; Uterine Cervical Neoplasms - pathology ; Uterine Cervical Neoplasms - therapy ; Uterine Cervical Neoplasms - virology ; Xenograft Model Antitumor Assays</subject><ispartof>Biochemical and biophysical research communications, 2015-10, Vol.465 (4), p.658-664</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. 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The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for degradation by the 26S proteasome. Loss of p53 triggers genomic instability and favors cancer development. Here, we generated recombinant adenovirus (Ad) vectors expressing artificial microRNAs directed against HPV16 E6 (Ad16_1) or HPV18 E6 (Ad18_2). E6-knockdown was observed in HeLa after treatment with Ad18_2 and in SiHa with Ad16_1. Western-blot experiments found an increase in p53 levels after treatment in both cell lines. Cell death was observed in both cell lines after knockdown of E6. Further analysis such as cleavage of caspases (3 and 7) as well as of PARP1 indicated that treated HeLa and SiHa cells underwent apoptosis. The growth of HeLa-derived tumors developed in nude mice was significantly reduced after intra-tumoral injection of Ad18_2. Therefore, vectorisation of artificial miRNA against E6 oncoprotein by means of recombinant adenoviruses might represent a valuable therapeutic approach for treating HPV-positive cancers.</description><subject>Adenoviridae - genetics</subject><subject>Adenovirus</subject><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>Cancer therapy</subject><subject>Cell Line</subject><subject>Cervical cancer</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Female</subject><subject>Gene Knockdown Techniques</subject><subject>Gene therapy</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors</subject><subject>HeLa Cells</subject><subject>Human health and pathology</subject><subject>Human papillomavirus</subject><subject>Human papillomavirus 16</subject><subject>Human papillomavirus 16 - genetics</subject><subject>Human papillomavirus 16 - pathogenicity</subject><subject>Human papillomavirus 18</subject><subject>Human papillomavirus 18 - genetics</subject><subject>Human papillomavirus 18 - pathogenicity</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>MicroRNAs - genetics</subject><subject>Oncogene Proteins, Viral - antagonists & inhibitors</subject><subject>Oncogene Proteins, Viral - genetics</subject><subject>Papillomavirus Infections - pathology</subject><subject>Papillomavirus Infections - therapy</subject><subject>Papillomavirus Infections - virology</subject><subject>Repressor Proteins - antagonists & inhibitors</subject><subject>Repressor Proteins - genetics</subject><subject>RNA interference</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Uterine Cervical Neoplasms - therapy</subject><subject>Uterine Cervical Neoplasms - virology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkdGK1DAUhoMo7rj6Al5ILvWi3XPSNGnBm2FZHWHQRVS8C2l6xs3YaWvSKezb-Cz7ZKbMupciBA5JvnP4z_8z9hIhR0B1sc-bJrhcAJY56BylfMRWCDVkAkE-ZisAUJmo8fsZexbjHgBRqvopOxNKSFS6XDG7DpPfeedtxw_eheHzx3Xk9of1fZz4dEN89iH9XSk-hmEi3y91Hn4St-MwTkP0kfv-7vfm-hsf023yM3Fne0eBO-q6-Jw92dku0ov7es6-vrv6crnJtp_ef7hcbzMnRTFlUlZYOFGWlU6nbhVUbaNbVbaOpKVWEzqp0VGhtSQSdVulbSQVQqBwqinO2ZvT3BvbmTH4gw23ZrDebNZbs7yBKKFWgDMm9vWJTbv8OlKczMHHRa3taThGg7pEAYWo9H-gKHQFulAJFSc02RhjoN2DDASzJGb2ZknMLIkZ0CbpT02v7ucfmwO1Dy1_I0rA2xNAybzZUzDReUr-tj6Qm0w7-H_N_wPcGKYa</recordid><startdate>20151002</startdate><enddate>20151002</enddate><creator>Bonetta, Anaëlle Charlotte</creator><creator>Mailly, Laurent</creator><creator>Robinet, Eric</creator><creator>Travé, Gilles</creator><creator>Masson, Murielle</creator><creator>Deryckere, François</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U9</scope><scope>H94</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0001-9765-805X</orcidid></search><sort><creationdate>20151002</creationdate><title>Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells</title><author>Bonetta, Anaëlle Charlotte ; Mailly, Laurent ; Robinet, Eric ; Travé, Gilles ; Masson, Murielle ; Deryckere, François</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-44813c255875879d608db7d65dce4aed7e1c471ce3774ee29d81144e32212c6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenoviridae - genetics</topic><topic>Adenovirus</topic><topic>Animals</topic><topic>Apoptosis - genetics</topic><topic>Cancer therapy</topic><topic>Cell Line</topic><topic>Cervical cancer</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Female</topic><topic>Gene Knockdown Techniques</topic><topic>Gene therapy</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors</topic><topic>HeLa Cells</topic><topic>Human health and pathology</topic><topic>Human papillomavirus</topic><topic>Human papillomavirus 16</topic><topic>Human papillomavirus 16 - genetics</topic><topic>Human papillomavirus 16 - pathogenicity</topic><topic>Human papillomavirus 18</topic><topic>Human papillomavirus 18 - genetics</topic><topic>Human papillomavirus 18 - pathogenicity</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>MicroRNAs - genetics</topic><topic>Oncogene Proteins, Viral - antagonists & inhibitors</topic><topic>Oncogene Proteins, Viral - genetics</topic><topic>Papillomavirus Infections - pathology</topic><topic>Papillomavirus Infections - therapy</topic><topic>Papillomavirus Infections - virology</topic><topic>Repressor Proteins - antagonists & inhibitors</topic><topic>Repressor Proteins - genetics</topic><topic>RNA interference</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Uterine Cervical Neoplasms - pathology</topic><topic>Uterine Cervical Neoplasms - therapy</topic><topic>Uterine Cervical Neoplasms - virology</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bonetta, Anaëlle Charlotte</creatorcontrib><creatorcontrib>Mailly, Laurent</creatorcontrib><creatorcontrib>Robinet, Eric</creatorcontrib><creatorcontrib>Travé, Gilles</creatorcontrib><creatorcontrib>Masson, Murielle</creatorcontrib><creatorcontrib>Deryckere, François</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bonetta, Anaëlle Charlotte</au><au>Mailly, Laurent</au><au>Robinet, Eric</au><au>Travé, Gilles</au><au>Masson, Murielle</au><au>Deryckere, François</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2015-10-02</date><risdate>2015</risdate><volume>465</volume><issue>4</issue><spage>658</spage><epage>664</epage><pages>658-664</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>High-risk human papillomavirus (HPV) types 16 and 18 are associated with more than 70% of cervical cancer cases. The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for degradation by the 26S proteasome. Loss of p53 triggers genomic instability and favors cancer development. Here, we generated recombinant adenovirus (Ad) vectors expressing artificial microRNAs directed against HPV16 E6 (Ad16_1) or HPV18 E6 (Ad18_2). E6-knockdown was observed in HeLa after treatment with Ad18_2 and in SiHa with Ad16_1. Western-blot experiments found an increase in p53 levels after treatment in both cell lines. Cell death was observed in both cell lines after knockdown of E6. Further analysis such as cleavage of caspases (3 and 7) as well as of PARP1 indicated that treated HeLa and SiHa cells underwent apoptosis. The growth of HeLa-derived tumors developed in nude mice was significantly reduced after intra-tumoral injection of Ad18_2. 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| subjects | Adenoviridae - genetics Adenovirus Animals Apoptosis - genetics Cancer therapy Cell Line Cervical cancer DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics Female Gene Knockdown Techniques Gene therapy Genetic Therapy Genetic Vectors HeLa Cells Human health and pathology Human papillomavirus Human papillomavirus 16 Human papillomavirus 16 - genetics Human papillomavirus 16 - pathogenicity Human papillomavirus 18 Human papillomavirus 18 - genetics Human papillomavirus 18 - pathogenicity Humans Life Sciences Mice Mice, Nude MicroRNAs - genetics Oncogene Proteins, Viral - antagonists & inhibitors Oncogene Proteins, Viral - genetics Papillomavirus Infections - pathology Papillomavirus Infections - therapy Papillomavirus Infections - virology Repressor Proteins - antagonists & inhibitors Repressor Proteins - genetics RNA interference Tumor Suppressor Protein p53 - metabolism Uterine Cervical Neoplasms - pathology Uterine Cervical Neoplasms - therapy Uterine Cervical Neoplasms - virology Xenograft Model Antitumor Assays |
| title | Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells |
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