3490

IGFBP7

AGM|FSTL2|IBP-7|IGFBP-7|IGFBP-7v|IGFBPRP1|MAC25|PSF|RAMSVPS|TAF;insulin-like growth factor binding protein 7;IGFBP7;insulin-like growth factor binding protein 7

IGF-binding protein 7|IGFBP-rP1|PGI2-stimulating factor|angiomodulin|insulin-like growth factor-binding protein 7|prostacyclin-stimulating factor|tumor-derived adhesion factor

4q12

protein-coding

Insulin-like growth factor-binding protein 7 (IGFBP7) has been identified as a tumor suppressor in solid tumors. In acute leukemia, the role of IGFBP7 is largely unknown. The authors used quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to investigate the expression level of IGFBP7 gene in bone marrow (BM) specimen from 66 children with acute myeloid leukemia (AML) at different stages and in 30 nonleukemia patients as control. Furthermore, U937 cells were transfected with siRNA-2 of IGFBP7 (as U937R) for 24 hours. Cocultureexperiment was performed to explore the impact of IGFBP7 gene in U937 cell adhesion, invasion, and migration in existing ECV304 cells, which mimicked the interaction between AML cells and endothelial cells. IGFBP7 expression at the initial diagnosed stage and relapse of AML was significantly higher than that ofcontrol (P < .001). The viable cell percentage in transfected cell was significantly decreased by 42% compared with control groups (P < .01). The percentage for U937R cells adherent to ECV304 cells was significantly lower thanthe control groups (P < .01). Matrigel study to quantify the invasive potential showed that U937R migrated to the lower chamber were significantly less than those in the parental control groups (P < .01). In summary, IGFBP7 aberrantly overexpressed in majority of AML at diagnosis and upon relapsed, but not at remission stage. IGFBP7 plays a positive contributing role in the interaction between leukemia cells and microenvironment, which may promote the leukemic cells' adhesion, invasion, and migration.

SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which servesas the diagnostic feature in malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. SMARCB1 is a core subunit of Swi/Snf chromatin remodeling complexes, and loss of SMARCB1 or other subunits of these complexes has been observed in a variety of tumor types. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors, which developed in Smarcb1 heterozygous p53-/- mice. We find that while re-introduction of Smarcb1 does not induce growth arrest, it restores sensitivity to programmed cell death and completely abolishes the ability of the tumor cells to grow as xenografts. We describe persistent activation of AKT signaling in Smarcb1-deficient cells, which stems from PI3K (phosphatidylinositol 3'-kinase)-mediated signaling and which contributes to thesurvival and proliferation of the tumor cells. We further demonstrate that inhibition of AKT is effective in preventing proliferation of Smarcb1-deficient cells in vitro and inhibits the development of xenografted tumors in vivo. Profiling Smarcb1-dependent gene expression, we find genes that require Smarcb1 and Swi/Snf for their expression to be enriched for extracellular matrix and cell adhesion functions. We find that Smarcb1 is required for transcriptional activation of Igfbp7, a member of the insulin-like growth factor-binding proteins family and a tumor suppressor in itself, and show that re-introduction of Igfbp7alone can hinder tumor development. Our results define a novel mechanism for Smarcb1-mediated tumorigenesis and highlight potential therapeutic targets.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.261.