A pathologic link between Wilms tumor suppressor gene, WT1, and IFI16.
The Wilms tumor gene (WT1) is mutated or deleted in patients with heredofamilial syndromes associated with the development of Wilms tumors, but is infrequently mutated in sporadic Wilms tumors. By comparing the microarray profiles of syndromic versus sporadic Wilms tumors and WT1-inducible Saos-2 osteosarcoma cells, we identified interferon-inducible protein 16 (IFI16), a transcriptional modulator, as a differentially expressed gene and a candidate WT1 target gene. WT1 induction in Saos-2 osteosarcoma cells led to strong induction of IFI16 expression and its promoter activity was responsive to the WT1 protein. Immunohistochemical analysis showed that IFI16 and WT1 colocalized in WT1-replete Wilms tumors, but not in normal human midgestation fetal kidneys, suggesting that the ability of WT1 to regulate IFI16 in tumors represented an aberrant pathologic relationship. In addition, endogenous IFI16 and WT1 interacted in vivo in two Wilms tumor cell lines. Furthermore, IFI16 augmented the transcriptional activity of WT1 on both synthetic and physiological promoters. Strikingly, short hairpin RNA (shRNA)-mediated knockdown of either IFI16 or WT1 led to decreased growth of Wilms tumor cells. These data suggest that IFI16 and WT1, in certain cellular context including sporadic Wilms tumors, may support cell survival.
Kim
Marianne K-H
MK
Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Mason
Jacqueline M
JM
Li
Chi-Ming
CM
Berkofsky-Fessler
Windy
W
Jiang
Le
L
Choubey
Divaker
D
Grundy
Paul E
PE
Tycko
Benjamin
B
Licht
Jonathan D
JD
D001859:Bone Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D014158:Transcription, Genetic; D015854:Up-Regulation; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000473:pathology*
D009687:Nuclear Proteins; D010750:Phosphoproteins; D025721:WT1 Proteins; C076700:IFI16 protein, human