title: Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.
abstract: Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Baxter
authors.forename: Qi
authors.initials: Q
authors.lastname: Lin
authors.forename: Hua
authors.initials: H
authors.lastname: Mao
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Yulun
authors.initials: Y
authors.lastname: Huang
authors.forename: Horatiu
authors.initials: H
authors.lastname: Voicu
authors.forename: Sivashankarappa
authors.initials: S
authors.lastname: Gurusiddappa
authors.forename: Jack M
authors.initials: JM
authors.lastname: Su
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.forename: Laszlo
authors.initials: L
authors.lastname: Perlaky
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dauser
authors.forename: Hon-chiu Eastwood
authors.initials: HC
authors.lastname: Leung
authors.forename: Karin M
authors.initials: KM
authors.lastname: Muraszko
authors.forename: Jason A
authors.initials: JA
authors.lastname: Heth
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
authors.forename: Murali
authors.initials: M
authors.lastname: Chintagumpala
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
mesh_terms: D000071916:AC133 Antigen; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016547:Kinesins; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; C108386:API5 protein, human; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C069077:BMI1 protein, human; C429530:DTL protein, human; C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; D006023:Glycoproteins; D009687:Nuclear Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D039102:Poly(A)-Binding Proteins; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C514435:KIF5C protein, human; D016547:Kinesins