Transcriptome signature of irreversible senescence in human papillomavirus-positive cervical cancer cells.
A frequent characteristic of human papillomavirus (HPV)-positive cervical cancers is the loss of viral E2 gene expression in HPV-infected cervical epithelial cells as a consequence of viral DNA integration into the cellular genome. The expression of E2 in HPV-positive cancer cells results in the repression of the viral E6/E7 oncogenes, activation of the p53 and pRB pathways, and a G1 cell cycle arrest, followed by induction of cellular senescence. The transcriptional consequences of E2-mediated cell cycle arrest that lead to senescence currently are unknown. Using conditional senescence induction in HeLa cells and microarray analysis, we describe here the expression profile of cells irreversibly committed to senescence. Our results provide insight into the molecular anatomy of senescence pathways and its regulation by HPV on-coproteins. These include the induction of the RAB vesicular transport machinery and a general down-regulation of chromatin regulatory molecules. The repression of tumor-specific G antigens during E2 senescence supports a reversal of the tumorigenic phenotype by E2 and the potential approach of tumor-specific G antigen-specific immunotherapy for cervical cancer.
Wells
Susanne I
SI
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Aronow
Bruce J
BJ
Wise
Trisha M
TM
Williams
Sarah S
SS
Couget
Jennifer A
JA
Howley
Peter M
PM
D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D052688:Bovine papillomavirus 1 / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics* / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D014158:Transcription, Genetic; D014412:Tumor Virus Infections / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004279:DNA, Viral; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012334:RNA, Neoplasm