10205-TB-8 ABSENCE OF RNF213 IN MEDULLOBLASTOMA INDUCES STARVATION RESISTANCE VIA GAS6 AND RESULTS IN TUMOR PROGRESSION

Abstract

Abstract RNF213 gene, initially identified as a disease-causing gene for moyamoya disease, has recently been recognized as a tumor regulator. We investigated the functions of RNF213 in tumorigenicity of medulloblastoma. Knockout of Rnf213 in Ptch1+/- spontaneous medulloblastoma mouse model increased the incidence of SHH type medulloblastoma from 19.8% to 76.5% (p<0.001) at 9 months. Subcutaneous implantation of the tumors showed that depletion of Rnf213 increased tumor formation frequency and tumor size. Unexpectedly, knockout of RNF213 in human Daoy cells decreased tumor growth and invasion in vitro. However, they were resistant to serum starvation and showed higher growth rate when implanted subcutaneously in nude mice. Transcriptome analysis of mouseRnf213-/- cells indicated that downregulation of Igf2 decreased tumor growth and upregulation of Gas6 increased resistance to starvation. In fact, GAS6 was upregulated in serum-free conditions and further upregulated in RNF213-/- cells. Survival advantage in serum starved conditions was lost by GAS6 knock-down in RNF213-/- Daoy cells. In conclusion, the effect of RNF213 depletion was context dependent. Resistance to starvation seems to outweigh growth retardation in normal conditions and is important for tumorigenicity and aggressiveness in vivo.