Project description:Insulin-like growth factor (IGF)-1 signaling and micro (mi)RNAs are relevant in mediating GBM progression. However, their roles in desensitizing GBM cells to TMZ are still unclear. We aimed to identify IGF-1-mediated miRNA regulatory networks that elicit TMZ insensitivity for GBM. By miRNA array analyses, totally 1,308 miRNAs were examined. The 93 upregulated and 148 downregulated miRNAs were identified in IGF-1-treated glioma cells.
Project description:The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through type I IGF receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-IIbinding and by inducing cell surface receptor down-regulation via internalization and degradation. In vitro, h10H5 exhibits anti-proliferative effects on cancer cell lines. In vivo, h10H5 demonstrates single-agent anti-tumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models, and even greater efficacy in combination with the chemotherapeutic agent Docetaxel or an anti-VEGF antibody. Anti-tumor activity of h10H5 is associated with decreased AKT activation and glucose uptake, and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors. Keywords: Gene expression changes as markers for drug activity
Project description:microRNA profiling of mouse small intestinal crypt cells comparing control untreated with cells treated with insulin growth factor-1 (IGF-1). IGF-1 stimulated cell proliferation, as observed in Brdu incoporation assay.
Project description:Previously, we showed that miRNA-190 (miR-190) is among the most upregulated miRNAs in all dormant tumors analyzed. Up-regulation of miR-190 led to prolonged tumor dormancy in otherwise fast-growing glioblastomas and osteosarcomas. In this study, we investigated transcriptional changes induced by miR-190 expression in cancer cells and show similar patterns of miR-190-mediated transcriptional reprogramming in both glioblastoma and osteosarcoma cells. The data suggests that miR-190-mediated effects rely on an extensive network of molecular changes in tumor cells and that miR-190 affects several transcriptional factors, tumor suppressor genes and interferon response pathways. For each cancer cell type, gene expression patterns in control cells that express GFP-only were compared to cells over-expressing microRNA-190.
Project description:The important role of IGF-1R in cancers has been well established. Classical model involves IGF-1/2 binding to IGF-1R, following activation of the PI3K/Akt pathway, thereby promoting cell proliferation, apoptosis inhibition and treatment resistance. While IGF-1R has become a promising target for cancer therapy, clinical disclosures subsequently have been less encouraging. The question is whether targeting IGF/IGF-1R still holds therapeutic potential. Here we show a novel mechanism that knockdown IGF-1R surprisingly triggers cytoplasmic viral RNA sensors MDA5 and RIG-1, leading to mitochondrial apoptosis in cancer. We analyzed MDA5 and RIG-1 in the intestinal epithelium of IGF-1R knockdown mice. Igf1r+/- mice demonstrated higher MDA5 and RIG-1 than WT mice. IGF-1R knockdown-triggered MDA5 and RIG-1 was further analyzed in human cancer and normal cells. Increased MDA5 and RIG-1 were clearly seen in the cytoplasm identified by immunofluoresce in the cells silenced IGF-1R. Block off IGF-1R downstream PI3K/Akt did not impact on MDA5 and RIG-1 expression. IGF-1R knockdown-triggered MDA5 and RIG-1 and their signaling pathways were similar to those of viral RNA mimetic poly(I:C) had. IGF-1R knockdown-triggered MDA5 and RIG-1 led to cancer apoptosis through activation of the mitochondrial pathway. In vivo assay, Igf1r+/- mice strongly resisted AOM-induced colonic tumorigenesis through triggering MDA¬5- and RIG-1-mediated apoptosis. Notably, RIG-I and MDA5-mediated proapoptotic signaling pathway is preferential active in cancer cells. These data suggest that targeting IGF-1R-triggered MDA5 and RIG-1 might have therapeutic potential for cancer treatment.
Project description:MicroRNA profiles were determined for surgically excised glioblastoma specimens and compared with normal adjacent tissue in the same patients
Project description:Orbital fibroblasts (OFs) are central to thyroid eye disease (TED) pathogenesis. Elevated insulin-like growth factor 1 receptor (IGF-1R) in TED OFs contributes to disease progression, but underlying mechanisms remain unclear. To elucidate IGF-1R-mediated signaling in OFs, we performed RNA-seq analysis after IGF-1 stimulation. Our data reveal that IGF-1 induces gene expression associated with cell proliferation, microtubule dynamics, and lipid metabolism while suppressing cell adhesion, senescence, and chromatin remodeling. Validation studies confirmed upregulation of CRABP2, a key regulator of retinoic acid signaling, and its role in IGF-1-induced OF migration. These findings uncover novel IGF-1R downstream effectors, providing insights into TED pathophysiology and potential therapeutic targets.
Project description:microRNA profiling of mouse small intestinal crypt cells comparing control untreated with cells treated with insulin growth factor-1 (IGF-1). IGF-1 stimulated cell proliferation, as observed in Brdu incoporation assay. Two condition experiment. Control vs IGF-1 treatment. Biological replicates: 3 control, 3 treated. Independently grown and harvested. One replicate per array