title: CUL2 overexpression driven by CUL2/E2F1/miR-424 regulatory loop promotes HPV16 E7 induced cervical carcinogenesis.
abstract: It has been shown that HPV16 E7, but not other genotypes, can bind to scaffold protein CUL2 during inducing cervical carcinogenesis, but the expression level, associated regulating mechanism, and potential carcinogenicity of CUL2 itself is still unknown as yet. Here, we demonstrated that CUL2 was specifically overexpressed in HPV16 positive cervical cancer cells and tissues, and CUL2 expression was significantly increased along with the cervical lesion progression and positively correlated with HPV16 E7. CUL2 knockdown slowed the growth of xenograft tumors in mouse models. Importantly, CUL2 specifically bound to HPV16 E7, but not HPV18 E7. Moreover, CUL2 acted as a direct target of miR-424, and reversely suppressed miR-424; E2F transcription factor 1 (E2F1) suppressed miR-424 expression; CUL2 bound to E2F1 and promoted E2F1 expression. Our results indicate the existence of a regulatory loop among CUL2, E2F1, and miR-424 in HPV16 positive cervical cancer cells. Our results suggest that E7 recruited CUL2, driven by CUL2/E2F1/miR-424 regulatory loop, is overexpressed and accelerates HPV16-induced cervical carcinogenesis. Our findings may serve as one of the explanations for a clinical phenomenon that HPV16 possesses the strongest cervical carcinogenicity among high-risk HPV genotypes.
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Junfen
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Second Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000235:genetics* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D011485:Protein Binding; D034622:RNA Interference; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: D020413:3' Untranslated Regions; C105153:CUL2 protein, human; D044842:Cullin Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16
keywords: CUL2; E2F1; HPV16 E7; cervical cancer; miR-424