AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs.
The events occurring during tumor formation and progression display similarities to some of the steps in embryonic morphogenesis. The family of AP-2 proteins consists of five different transcription factors (alpha, beta, gamma, delta, and epsilon) that play relevant roles in embryonic development, as demonstrated by the phenotypes of the corresponding knockout mice. Here, we show that AP-2alpha and AP-2gamma proteins play an essential role in tumorigenesis. Down-modulation of AP-2 expression in tumor cells by RNA interference (RNAi) led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. Most of these biological modulations were rescued by AP-2 overexpression. We observed that increased xenotransplant growth was mostly due to highly enhanced proliferation of the tumor cells together with reduced innate immune cell recruitment. Moreover, we showed that migration impairment was mediated, at least in part, by secreted factors. To identify the genetic programs involved in tumorigenesis, we performed whole genome microarray analysis of AP-2alpha knockdown cells and observed that AP-2alpha regulates specific genes involved in cell cycle, cell death, adhesion, and migration. In particular, we showed that ESDN, EREG, and CXCL2 play a major role in AP-2 controlled migration, as ablation of any of these genes severely altered migration.
Orso
Francesca
F
Institute for Cancer Research and Treatment, University of Torino, Via Nizza, 52, 10126 Torino, Italy.
Penna
Elisa
E
Cimino
Daniela
D
Astanina
Elena
E
Maione
Federica
F
Valdembri
Donatella
D
Giraudo
Enrico
E
Serini
Guido
G
Sismondi
Piero
P
De Bortoli
Michele
M
Taverna
Daniela
D
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D054426:Chemokine CXCL2 / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D066260:Epiregulin; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; C436326:DCBLD2 protein, human; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2; D004815:Epidermal Growth Factor