科研之友
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摘要
P>Malignant gliomas are highly invasive neuroepithelial tumors where the tendency to invade and migrate away from the primary tumor mass is thought to be a leading cause of tumor recurrence and treatment failures. Autocrine signals produced by secreted factors that signal through receptors on the tumor are known to contribute to the invasiveness. Glial cell line-derived neurotrophic factor and GDNF family receptor alpha 1 (GFR alpha 1) are over-expressed in human gliomas. We have previously reported that human gliomas express high levels of GFR alpha 1b, an alternatively spliced isoform of GFR alpha 1. However, the functional significance of GFR alpha 1b in glioma behaviors is currently unknown. In this study, we have designed isoform-specific small-interfering RNA to knockdown the highly homologous GFR alpha 1a or GFR alpha 1b isoform efficiently in malignant C6 glioma cells. Unexpectedly, the knockdown of GFR alpha 1b but not GFR alpha 1a induced cell elongation and inhibited C6 cell migration and invasion in vitro. In addition, GFR alpha 1b was found to regulate the expression of RhoA small GTPase, which was required for migration of C6 cells. The decreases in RhoA expression and cell migration after GFR alpha 1b knockdown were attenuated by small-interfering RNA -resistant GFR alpha 1b but not GFR alpha 1a, further demonstrating the specific role of GFR alpha 1b in glioma migration. Interestingly, the knockdown of NCAM but not receptor tyrosine kinase Ret resulted in the reduction of RhoA expression and C6 cell migration. Taken together, these unanticipated results indicate that GFR alpha 1b is involved in glioma migration through glial cell line-derived neurotrophic factor -GFR alpha 1b-NCAM signaling complex and modulation of RhoA expression.
- 出版日期2010-11
