SCCRO promotes glioma formation and malignant progression in mice.
Originally identified as an oncogene activated by amplification in squamous cell carcinomas, several lines of evidence now suggest that squamous cell carcinoma-related oncogene (SCCRO; aka DCUN1D1) may play a role in the pathogenesis of a wide range of human cancers including gliomas. SCCRO's oncogenic function is substantiated by its ectopic expression, resulting in transformation of cells in culture and xenograft formation in nude mice. The aim of this study was to assess the in vivo oncogenicity of SCCRO in a murine model. Ubiquitous expression of SCCRO resulted in early embryonic lethality. Because SCCRO overexpression was detected in human gliomas, its in vivo oncogenic activity was assessed in an established murine glioma model. Conditional expression of SCCRO using a replication-competent ASLV long terminal repeat with splice acceptor/nestin-(tumor virus-A) tv-a model system was not sufficient to induce tumor formation in a wild-type genetic background, but tumors formed with increasing frequency and decreasing latency in facilitated background containing Ink4a deletion alone or in combination with PTEN loss. Ectopic expression of SCCRO in glial progenitor cells resulted in lower-grade gliomas in Ink4a(-/-) mice, whereas its expression in Ink4a(-/-)/PTEN(-/-) background produced high-grade glioblastoma-like lesions that were indistinguishable from human tumors. Expression of SCCRO with platelet-derived growth factor-beta (PDGF-beta) resulted in an increased proportion of mice forming glioblastoma-like tumors compared with those induced by PDGF-beta alone. This work substantiates SCCRO's function as an oncogene by showing its ability to facilitate malignant transformation and carcinogenic progression in vivo and supports a role for SCCRO in the pathogenesis of gliomas and other human cancers.
Broderick
Stephen R
SR
Thoracic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.
Golas
Benjamin J
BJ
Pham
Duykhanh
D
Towe
Christopher W
CW
Talbot
Simon G
SG
Kaufman
Andrew
A
Bains
Sarina
S
Huryn
Laryssa A
LA
Yonekawa
Yoshihiro
Y
Carlson
Diane
D
Hambardzumyan
Dolores
D
Ramanathan
Yegnanarayana
Y
Singh
Bhuvanesh
B
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005804:Genes, Lethal; D005910:Glioma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000502:physiology; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019941:Cyclin-Dependent Kinase Inhibitor p16; C408631:DCUN1D1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse