Mojgan Padash Barmchi , Rami N. Hassan , Mehrnaz Afkhami , John P. Masly , Harrison Brown , Quincy P. Collins , Michael J. Grunsted
{"title":"hpv18诱导的果蝇模型揭示E6致癌基因调控NF-κB和Wnt抑制细胞凋亡","authors":"Mojgan Padash Barmchi , Rami N. Hassan , Mehrnaz Afkhami , John P. Masly , Harrison Brown , Quincy P. Collins , Michael J. Grunsted","doi":"10.1016/j.tvr.2025.200316","DOIUrl":null,"url":null,"abstract":"<div><div>Cancers caused by high-risk human papillomavirus (HPV) remain a significant health threat resulting in more than 300,000 deaths, annually. Persistent expression of two HPV oncogenes, E6 and E7, are necessary for cancer development and progression. E6 has several functions contributing to tumorigenesis one of which is blocking programmed cell death, apoptosis. The detailed mechanism of anti-apoptosis function of E6 is not fully understood. Here, using a <em>Drosophila</em> model of HPV18E6 and the human UBE3A-induced pathogenesis, we show that anti-apoptotic function of E6 is conserved in <em>Drosophila</em>. We demonstrate that the <em>Drosophila</em> homologs of human NF-κB transcription factors, Dorsal and Dif are proapoptotic. They induce the expression of Wingless (Wg, the <em>Drosophila</em> homolog of human Wnt), leading to apoptosis. Our results indicate that E6 oncogene inhibits apoptosis by downregulating the expression of Wg, Dorsal, and Dif. Additionally, we find that Dorsal and Dif, not only promote apoptosis but also regulate autophagy and necrosis. Dorsal promotes autophagy while Dif counteracts it, inducing the formation of acidic vacuoles and necrosis. Interestingly, although E6 blocks the proapoptotic function of Dorsal and Dif, it lacks the ability to interfere with their role in apoptosis-independent cell death. Given the high conservation of NF-κB transcription factors our results provide new insight into potential mechanisms mediated by NF-κB to intervene with cell immortalization action of E6 oncoprotein in HPV-infected cells.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200316"},"PeriodicalIF":4.7000,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Drosophila model of HPV18-Induced pathogenesis reveals a role for E6 oncogene in regulation of NF-κB and Wnt to inhibit apoptosis\",\"authors\":\"Mojgan Padash Barmchi , Rami N. Hassan , Mehrnaz Afkhami , John P. Masly , Harrison Brown , Quincy P. Collins , Michael J. Grunsted\",\"doi\":\"10.1016/j.tvr.2025.200316\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Cancers caused by high-risk human papillomavirus (HPV) remain a significant health threat resulting in more than 300,000 deaths, annually. Persistent expression of two HPV oncogenes, E6 and E7, are necessary for cancer development and progression. E6 has several functions contributing to tumorigenesis one of which is blocking programmed cell death, apoptosis. The detailed mechanism of anti-apoptosis function of E6 is not fully understood. Here, using a <em>Drosophila</em> model of HPV18E6 and the human UBE3A-induced pathogenesis, we show that anti-apoptotic function of E6 is conserved in <em>Drosophila</em>. We demonstrate that the <em>Drosophila</em> homologs of human NF-κB transcription factors, Dorsal and Dif are proapoptotic. They induce the expression of Wingless (Wg, the <em>Drosophila</em> homolog of human Wnt), leading to apoptosis. Our results indicate that E6 oncogene inhibits apoptosis by downregulating the expression of Wg, Dorsal, and Dif. Additionally, we find that Dorsal and Dif, not only promote apoptosis but also regulate autophagy and necrosis. Dorsal promotes autophagy while Dif counteracts it, inducing the formation of acidic vacuoles and necrosis. Interestingly, although E6 blocks the proapoptotic function of Dorsal and Dif, it lacks the ability to interfere with their role in apoptosis-independent cell death. Given the high conservation of NF-κB transcription factors our results provide new insight into potential mechanisms mediated by NF-κB to intervene with cell immortalization action of E6 oncoprotein in HPV-infected cells.</div></div>\",\"PeriodicalId\":52381,\"journal\":{\"name\":\"Tumour Virus Research\",\"volume\":\"19 \",\"pages\":\"Article 200316\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-03-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tumour Virus Research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666679025000047\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"VIROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tumour Virus Research","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666679025000047","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"VIROLOGY","Score":null,"Total":0}
Drosophila model of HPV18-Induced pathogenesis reveals a role for E6 oncogene in regulation of NF-κB and Wnt to inhibit apoptosis
Cancers caused by high-risk human papillomavirus (HPV) remain a significant health threat resulting in more than 300,000 deaths, annually. Persistent expression of two HPV oncogenes, E6 and E7, are necessary for cancer development and progression. E6 has several functions contributing to tumorigenesis one of which is blocking programmed cell death, apoptosis. The detailed mechanism of anti-apoptosis function of E6 is not fully understood. Here, using a Drosophila model of HPV18E6 and the human UBE3A-induced pathogenesis, we show that anti-apoptotic function of E6 is conserved in Drosophila. We demonstrate that the Drosophila homologs of human NF-κB transcription factors, Dorsal and Dif are proapoptotic. They induce the expression of Wingless (Wg, the Drosophila homolog of human Wnt), leading to apoptosis. Our results indicate that E6 oncogene inhibits apoptosis by downregulating the expression of Wg, Dorsal, and Dif. Additionally, we find that Dorsal and Dif, not only promote apoptosis but also regulate autophagy and necrosis. Dorsal promotes autophagy while Dif counteracts it, inducing the formation of acidic vacuoles and necrosis. Interestingly, although E6 blocks the proapoptotic function of Dorsal and Dif, it lacks the ability to interfere with their role in apoptosis-independent cell death. Given the high conservation of NF-κB transcription factors our results provide new insight into potential mechanisms mediated by NF-κB to intervene with cell immortalization action of E6 oncoprotein in HPV-infected cells.