Introduction: Medulloblastoma (MB) is a malignant pediatric brain tumor that arises in the cerebellar granular neurons. Sonic Hedgehog subtype of MB (SHH-MB) is one of the major subtypes of MB in the clinic. However, the molecular mechanisms underlying MB tumorigenesis are still not fully understood.
Aims: Our previous work demonstrated that the receptor for activated C kinase 1 (Rack1) is essential for SHH signaling activation in granule neuron progenitors (GNPs) during cerebellar development. To investigate the potential role of Rack1 in MB development, human MB tissue array and SHH-MB genetic mouse model were used to study the expression of function of Rack1 in MB pathogenesis.
Results: We found that the expression of Rack1 was significantly upregulated in the majority of human cerebellar MB tumors. Genetic ablation of Rack1 expression in SHH-MB tumor mice could significantly inhibit MB proliferation, reduce the tumor size, and prolong the survival of tumor rescue mice. Interestingly, neither apoptosis nor autophagy levels were affected in Rack1-deletion rescue mice compared to WT mice, but the expression of Gli1 and HDAC2 was significantly decreased suggesting the inactivation of SHH signaling pathway in rescue mice.
Conclusion: Our results demonstrated that Rack1 may serve as a potential candidate for the diagnostic marker and therapeutic target of MB, including SHH-MB.
Keywords: GNPs; Gli1; Sonic hedgehog; medulloblastoma; rack1.
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