Open AccessDisruption of rack1 suppresses SHH‐type medulloblastoma formation in mice
Author(s) -
Liu Fengjiao,
Shao Jingyuan,
Yang Haihong,
Yang Guochao,
Zhu Qian,
Wu Yan,
Zhu Lingling,
Wu Haitao
Publication year - 2021
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13728
Subject(s) - medulloblastoma , sonic hedgehog , gli1 , cancer research , biology , cerebellum , gli2 , downregulation and upregulation , patched , microbiology and biotechnology , signal transduction , hedgehog signaling pathway , neuroscience , genetics , gene
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.