RbAp48 is a critical mediator controlling the transforming activity of human papillomavirus type 16 in cervical cancer.
Although human papillomavirus (HPV) infections are the primary cause of cervical cancer, the molecular mechanism by which HPV induces cervical cancer remains largely unclear. We used two-dimensional electrophoresis with mass spectrometry to study protein expression profiling between HPV16-positive cervical mucosa epithelial H8 cells and cervical cancer Caski cells to identify 18 differentially expressed proteins. Among them, retinoblastoma-binding protein 4 (RbAp48) was selected, and its differentiation expression was verified with both additional cervical cancer-derived cell lines and human tissues of cervical intraepithelial neoplasia and cervical cancer. Suppression of RbAp48 using small interfering RNA approach in H8 cells significantly stimulated cell proliferation and colony formation and inhibited senescence-like phenotype. Remarkably, H8 cells acquired transforming activity if RpAp48 was suppressed, because H8 cells stably transfected with RbAp48 small interfering RNA led to tumor formation in nude mice. In addition, overexpression of RbAp48 significantly inhibited cell growth and tumor formation. This RbAp48-mediated transformation of HPV16 is probably because of the regulation by RbAp48 of tumor suppressors retinoblastoma and p53, apoptosis-related enzymes caspase-3 and caspase-8, and oncogenic genes, including E6, E7, cyclin D1 (CCND1), and c-MYC. In brief, RbAp48, previously unknown in cervical carcinogenesis, was isolated in a global screen and identified as a critical mediator controlling the transforming activity of HPV16 in cervical cancer.
Kong
Li
L
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York 10003, USA.
Yu
Xiu-Ping
XP
Bai
Xiao-Hui
XH
Zhang
Wei-Fang
WF
Zhang
Yan
Y
Zhao
Wei-Ming
WM
Jia
Ji-Hui
JH
Tang
Wei
W
Zhou
Ya-Bin
YB
Liu
Chuan-ju
CJ
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D053181:Caspase 8 / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D056505:Retinoblastoma-Binding Protein 4; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000821:virology
D002352:Carrier Proteins; D056741:Cyclin D; D016213:Cyclins; C068651:E6 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016271:Proto-Oncogene Proteins c-myc; C082637:RBBP4 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D056505:Retinoblastoma-Binding Protein 4; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D053148:Caspase 3; D053181:Caspase 8