TY - JOUR
T1 - Interfering with long non-coding RNA MIR22HG processing inhibits glioblastoma progression through suppression of Wnt/b-catenin signalling
AU - Han, Mingzhi
AU - Wang, Shuai
AU - Fritah, Sabrina
AU - Wang, Xu
AU - Zhou, Wenjing
AU - Yang, Ning
AU - Ni, Shilei
AU - Huang, Bin
AU - Chen, Anjing
AU - Li, Gang
AU - Miletic, Hrvoje
AU - Thorsen, Frits
AU - Bjerkvig, Rolf
AU - Li, Xingang
AU - Wang, Jian
N1 - Publisher Copyright:
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long noncoding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/b-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/b-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.
AB - Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long noncoding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/b-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/b-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.
KW - Glioblastoma
KW - LncRNA
KW - MiRNA
KW - Small-molecule inhibitor
KW - Wnt/b-catenin signalling
UR - http://www.scopus.com/inward/record.url?scp=85079250201&partnerID=8YFLogxK
U2 - 10.1093/brain/awz406
DO - 10.1093/brain/awz406
M3 - Article
C2 - 31891366
AN - SCOPUS:85079250201
SN - 0006-8950
VL - 143
SP - 512
EP - 530
JO - Brain
JF - Brain
IS - 2
ER -