Epigenetic silencing of miR-338 facilitates glioblastoma progression by de-repressing the pyruvate kinase M2-β-catenin axis.

Abstract

Glioblastoma is the most malignant type of brain tumor, and its high invasiveness and multiplication severely shortens patients' overall survival. The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. We used computational target gene prediction, in vitro cell culture, immunoblotting, quantitative real-time PCR, ATP measurements, luciferase reporter assays, wound-healing assays, Transwell assays, RNA immunoprecipitation PCR, co-immunoprecipitation, flow cytometry and tumor xenografts to study the regulation of the PKM2/β-catenin axis in glioma. PKM2 was predicted to be a potential target of miR-338. MiR-338 was downregulated in high-grade gliomas due to hypermethylation of CpG islands in its promoter, and ectopic expression of miR-338 inhibited cell proliferation, invasion and ATP generation. MiR-338 inhibited PKM2 expression by binding to the 3' untranslated region of PKM2, which ultimately prevented binding of PKM2 to β-catenin and reduced T-cell factor/lymphoid enhancer factor reporter gene transcriptional activity. MiR-338 also inhibited PKM2 expression, attenuated glioma growth and prolonged survival in an animal model. These results confirm that miR-338, a tumor suppressor, suppresses the PKM2/β-catenin axis and is downregulated in glioblastoma. This provides a theoretical basis for glioma-targeting therapy.

• Authors: Bo Han, Xiangqi Meng, Hui Chen, Lingchao Chen, Xing Liu, Hongjun Wang, Daming Liu, Fei Gao, Lin Lin, Jianguang Ming, Bo Sun, Shi Yin, Ruijia Wang, Pengfei Wu, Jinquan Cai, Chuanlu Jiang
• Journal: Aging (Aging (Albany NY)) Vol. 9 Issue 8 Pg. 1885-1897 (08 02 2017) ISSN: 1945-4589 [Electronic] United States
• PMID: 28858851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• CTNNB1 protein, human
• Carrier Proteins
• MIRN338 microRNA, human
• Membrane Proteins
• MicroRNAs
• Thyroid Hormones
• beta Catenin

Topics

• 3' Untranslated Regions
• Animals
• Binding Sites
• Brain Neoplasms (enzymology, genetics, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• CpG Islands
• DNA Methylation
• Disease Progression
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice, Nude
• MicroRNAs (genetics)
• Neoplasm Grading
• Neoplasm Invasiveness
• Promoter Regions, Genetic
• Signal Transduction
• Thyroid Hormones (genetics, metabolism)
• Time Factors
• Transcription, Genetic
• Tumor Burden
• beta Catenin (genetics, metabolism)
• Thyroid Hormone-Binding Proteins