Oncogene database

3481

IGF2

insulin-like growth factor 2;IGF2;insulin-like growth factor 2

T3M-11-derived growth factor|insulin-like growth factor 2 (somatomedin A)|insulin-like growth factor II|insulin-like growth factor type 2

11p15.5

protein-coding

Synovial sarcoma is an aggressive soft tissue tumor characterized by a specific chromosomal translocation between chromosome 18 and X. This translocation can generate a fusion transcript encoding SYT-SSX1, a transforming oncoprotein. We present evidence that SYT-SSX1 induces insulin-like growth factor II expression in fibroblast cells. SYT-SSX2, a fusion also frequently found in synovial sarcoma, is necessary for maintaining Igf2 expression in the synovial sarcoma cell line, and the increased IGF2 synthesis protects cells from anoikis and is required for tumor formation in vivo. We also found a loss of imprinting (LOI) for Igf2 in a limited number of primary synovial sarcomas despite demethylation of CpG dinucleotides critical for maintaining imprinting. These findings suggest that inhibition of the IGF2/IGF1-R signaling pathway may represent a significant therapeutic modality for treating synovial sarcoma.

The protumorigenic insulin-like growth factor (IGF)-II is highly expressed in a significant fraction of human hepatocellular carcinomas (HCC). However, a functional dissection that clarifies the contribution of IGF-II-binding receptors in tumor progression and a respective molecular characterization of IGF-II signaling has not been performed. Therefore, expression of IGF-II and its receptors IGF-receptor type I (IGF-IR) and insulin receptor (IR) was efficiently blocked using small interfering RNA (siRNA) in HCC cells. Despite functional IR-signaling, oncogenic IGF-II effects such as tumor cell viability, proliferation, and anti-apoptosis were solely transmitted by IGF-IR. Although IGF-II signaling was previously not described in the context of HCC cell migration, the IGF-II-dependent expression profile displayed a high percentage of genes involved in cell motility and adhesion. Indeed, IGF-II overexpression promoted HCC cell migration, especially in synergy with hepatocyte growth factor (HGF). The therapeutic relevance of IGF-II/IGF-IR signaling was tested in vitro and in a murine xenograft transplantation model using the IGF-IR inhibitor picropodophyllin (PPP). IGF-IR inhibition by small molecule treatment efficiently reduced IGF-II-dependent signaling and ALL protumorigenic properties of the IGF-II/IGF-IR pathway. CONCLUSION: In human HCC cells, IGF-IR but not IR is involved in oncogenic IGF-II signaling. Autocrine stimulation of IGF-II induces HCC motility by integration of paracrine signals for full malignant competence. Thus, activation of IGF-II/IGF-IR signaling is likely a progression switch selected by function that promotes tumor cell dissemination and aggressive tumor behavior.

Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma.