Loss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I.

Abstract

Malignant glioma is the most common brain tumor. The molecular basis of glioma tumorigenicity has not been defined. Cultured glioma cells accumulate hg levels of insulin-like growth factor I (IGF-I) transcripts. We asked whether IGF-I expression is coupled to tumorigenicity, using a combined in vivo/in vitro system employing antisense RNA for IGF-I. An antisense IGF-I expression construct in an expression vector that incorporates Epstein-Barr virus replicative signals and the ZnSO4-inducible metallothionein I t scriptional promoter was assembled. Stable glioma transfectants were derived from C6 glioma cells, which constitutively express IGF-I. B-104 neuroblastoma cells, derived originally from the same tumor but not expressing IGF-I, were also trasected as controls. In the absence of ZnSO4, the C6 traectants expressed high levels of IGF-I mRNA and protein as detected by in situ hybridization and immunocyochemlsry, respectively. Addition ofZnSO4 in the culture medium resulted in hig levels of antisense transcript accumulation and dramatically de

Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas

“…These include SV40 T antigen, activated Ha-ras oncogene (Sell et al, 1993, bovine papilloma virus E5 protein (Morrione et al, 1995), human papilloma virus (Steller et al, 1996), activated c-src , and overexpressed growth factor receptors, including EGF , PDGF (DeAngelis et al, 1995) and insulin (Miura et al, 1995) receptors. In agreement with these ®ndings, antibodies against the IGF-IR (Kalebic et al, 1994), antisense expression plasmids (Trojan et al, 1992(Trojan et al, , 1993Resnico et al, 1994;Shapiro et al, 1994), and dominant negative mutants of the IGF-IR (Prager et al, 1994;Burgaud et al, 1995;Reiss et al, 1998aReiss et al, , 1999 can attenuate malignant tumor growth by inducing apoptosis, and/or by inhibiting cell proliferation.…”

“…The presence of an active IGF system has been shown in astrocytomas (Antoniades et al, 1992), glioblastomas (Trojan et al, 1992(Trojan et al, , 1993Resnico et al, 1994), meningiomas (Antoniades et al, 1992), and neuroblastoma cells (Martin et al, 1992).…”

MicroRNA-21 Promotes Glioblastoma Tumorigenesis by Down-regulating Insulin-like Growth Factor-binding Protein-3 (IGFBP3)

“…By modulating the bioavailability of IGFs, IGFBPs regulate tumor growth and invasion (24). Overexpression of soluble and its receptor IGF-1R has been detected in several cancers, including prostate cancer, melanoma, and GBM (25)(26)(27)(28). IGFR1 signaling has also been found to mediate resistance to chemotherapy and radiation (29 -32).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…However, an incomplete reduction of IGF-1R expression as well as unwanted effects on INSR levels have been described, which is possibly owing to the poor accessibility of the target transcripts by the oligonucleotides (Bohula et al, 2003). Besides targeting the bioactivity and bioavailability of IGF-1R, several approaches are aimed to modulate the ligand (IGF-I and IGF-II) expression and bioavailability using antisense techniques (Trojan et al, 1992(Trojan et al, , 1993, neutralizing antibodies (Su et al, 1999;Goya et al, 2004;Lund et al, 2004;Miyamoto et al, 2005) and induction of IGF BPs (Martin et al, 1999;Gray et al, 2000;Zi et al, 2000).…”