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 |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work