Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance Journal Article


Authors: Peng, K. L.; Vasudevan, H. N.; Lockney, D. T.; Baum, R.; Hendrickson, R. C.; Raleigh, D. R.; Schmitt, A. M.
Article Title: Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance
Abstract: Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.
Keywords: genetics; metabolism; microrna; sonic hedgehog protein; hedgehog proteins; membrane proteins; carcinogenesis; rna binding protein; rna-binding proteins; medulloblastoma; membrane protein; micrornas; cerebellar neoplasms; cerebellum tumor; humans; human; long noncoding rna; long untranslated rna; rna, long noncoding; metadherin; miat; mtdh protein, human
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 119
Issue: 37
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2022-09-13
Start Page: e2203738119
Language: English
DOI: 10.1073/pnas.2203738119
PUBMED: 36067288
PROVIDER: scopus
PMCID: PMC9478675
DOI/URL:
Notes: Article -- Export Date: 3 October 2022 -- Source: Scopus
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  1. Adam Michael Schmitt
    50 Schmitt
  2. Kai-lin Peng
    3 Peng
  3. Rachel Baum
    2 Baum