3479

IGF1

IGF-I|IGF1A|IGFI;insulin-like growth factor 1 (somatomedin C);IGF1;insulin-like growth factor 1 (somatomedin C)

IGF-IA|IGF-IB|MGF|insulin-like growth factor 1|insulin-like growth factor I|insulin-like growth factor IA|insulin-like growth factor IB|mechano growth factor|somatomedin-C

12q23.2

protein-coding

Recent findings have indicated that Insulin-like growth factors (IGF-I and IGF-II) may play a role in neoplasia. expression of their genes, which are highly complex structures, is tissue-specific and developmentally regulated. The purpose of the present study was to determine whether a relationship exists between tumorigenesis and the structure and expression of IGF genes. The structures of the IGF-I and IGF-II genes were investigated in 40 tumors by Southern blot analysis but no obvious re-arrangements (such as amplification or deletion) wereobserved in any of the tissues investigated. DNA methylation was also studied, using the enzyme Avall. The extent of DNA methylation of the IGF genes was highly variable in most of the tumors, as was the level of mRNA expression. A relationship could be detected between IGF over-expression and gene demethylation in tumors associated with hypoglycemia and in certain hepatocarcinomas. Loss of heterozygosity has been reported in the 11p15 region of some childhood tumors. The present findings provide further evidence of this loss of heterozygosity forthe IGF-II gene and show an imbalance in the leukocyte alleles in several childhood tumors. Likewise, an imbalance in the alleles was noted in several adult tumors, including hepatocarcinomas and breast cancers. This suggests that in certain adult tumors alterations of the IGF-II gene may be associated with tumorigenesis, but in other tumors another mechanism may be involved.

OBJECTIVE: Overexpression of IGF-I occurs in tumors diagnosed in childhood (osteosarcoma, Wilms tumor, neuroblastoma, etc.) and in adults (breast, ovaries,colon and prostate cancer). The aim of our study was to establish the prevalenceof malignancies in states of congenital IGF-I deficiency. SUBJECTS: We surveyed 222 patients with congenital IGF-I deficiency (Laron syndrome, GH gene deletion,GHRH receptor defects and IGF-I resistance) and 338 first and second-degree relatives. RESULTS: None of the IGF-I deficient patients had cancer, whereas 9-24% of the family members had a history of malignancy. CONCLUSIONS: CongenitalIGF-I deficiency acts as a protecting factor for the development of cancer.

OBJECTIVE: Overexpression of IGF-I occurs in tumors diagnosed in childhood (osteosarcoma, Wilms tumor, neuroblastoma, etc.) and in adults (breast, ovaries,colon and prostate cancer). The aim of our study was to establish the prevalenceof malignancies in states of congenital IGF-I deficiency. SUBJECTS: We surveyed 222 patients with congenital IGF-I deficiency (Laron syndrome, GH gene deletion,GHRH receptor defects and IGF-I resistance) and 338 first and second-degree relatives. RESULTS: None of the IGF-I deficient patients had cancer, whereas 9-24% of the family members had a history of malignancy. CONCLUSIONS: CongenitalIGF-I deficiency acts as a protecting factor for the development of cancer.

OBJECTIVE: Overexpression of IGF-I occurs in tumors diagnosed in childhood (osteosarcoma, Wilms tumor, neuroblastoma, etc.) and in adults (breast, ovaries,colon and prostate cancer). The aim of our study was to establish the prevalenceof malignancies in states of congenital IGF-I deficiency. SUBJECTS: We surveyed 222 patients with congenital IGF-I deficiency (Laron syndrome, GH gene deletion,GHRH receptor defects and IGF-I resistance) and 338 first and second-degree relatives. RESULTS: None of the IGF-I deficient patients had cancer, whereas 9-24% of the family members had a history of malignancy. CONCLUSIONS: CongenitalIGF-I deficiency acts as a protecting factor for the development of cancer.

BACKGROUND: Insulin-like growth factor (IGF) system as regulator for cellular proliferation is of particular interest in search for new prognostic approaches in cancer treatment. PROCEDURE: We analyzed the mRNA expression profile of IGF-I, -II, and IGFBP-2, -3 in 50 children with previously untreated AML (mean age 10.8+/- 4.8 years; patients in CCR n = 20, patients with relapse during later courseof disease n = 15). MNC samples from peripheral blood as well as bone marrow of healthy donors were used as controls. RESULTS: IGFBP-2 expression was significantly higher in AML cells than in healthy cells of peripheral MNC (P < 0.001) and of bone marrow cells (P < 0.01). Conversely, AML cells showed significantly lower IGFBP-3 and IGF-I gene expression compared to controls (P = 0.02; P < 0.001). Patients with relapse (median +/- range: 0.0929 +/- 0.049) during later course of disease demonstrated higher IGFBP-2 expression compared to patients in CCR (0.0121 +/- 0.047; P = 0.06) at time of diagnosis. A multivariate analysis identified the IGFBP-2 mRNA expression as an independent factor for theprediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 mRNA level >0.1000 was 28%; whereas, the probability of RFS in patients with IGFBP-2 mRNA level <0.1000 was 62% (P = 0.04, log-rank test). No prognostic influence could be found for the other investigated genes. CONCLUSIONS: Results identified different expressions of IGF components between normal and AML cells. Patients with IGFBP-2 mRNA levels up to 0.1000 (relative to KG1 cell line) more likely developed a relapse. Identification of these patients at diagnosis may allow more individualized treatment.#CI- (c) 2007 Wiley-Liss, Inc.

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with criticalfunctions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences.However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven byEWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, ALL of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGFsignaling.