MiR-330-mediated regulation of SH3GL2 expression enhances malignant behaviors of glioblastoma stem cells by activating ERK and PI3K/AKT signaling pathways

Yilong Yao; Yixue Xue; Jun Ma; Chao Shang; Ping Wang; Libo Liu; Wenjing Liu; Zhen Li; Shengtao Qu; Zhiqing Li; Yunhui Liu

doi:10.1371/journal.pone.0095060

MiR-330-mediated regulation of SH3GL2 expression enhances malignant behaviors of glioblastoma stem cells by activating ERK and PI3K/AKT signaling pathways

PLoS One. 2014 Apr 15;9(4):e95060. doi: 10.1371/journal.pone.0095060. eCollection 2014.

Authors

Yilong Yao¹, Yixue Xue², Jun Ma², Chao Shang², Ping Wang², Libo Liu², Wenjing Liu³, Zhen Li¹, Shengtao Qu¹, Zhiqing Li⁴, Yunhui Liu¹

Affiliations

¹ Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China.
² Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang, Liaoning Province, People's Republic of China.
³ Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, People's Republic of China.
⁴ Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province, People's Republic of China.

Abstract

MicroRNAs are currently considered as an active and rapidly evolving area for the treatment of tumors. In this study, we elucidated the biological significance of miR-330 in glioblastoma stem cells (GSCs) as well as the possible molecular mechanisms. SH3GL2 is mainly distributed in the central nervous system and considered to be a tumor suppressor in many tumors. In the present study, we identified miR-330 as a potential regulator of SH3GL2 and we found that it was to be inversely correlated with SH3GL2 expression in GSCs which were isolated from U87 cell lines. The expression of miR-330 enhanced cellular proliferation, promoted cell migration and invasion, and dampened cell apoptosis. When the GSCs were co-transfected with the plasmid containing short hairpin RNA directed against human SH3GL2 gene and miR-330 mimic, we found that miR-330 promoted the malignant behavior of GSCs by down-regulating the expression of SH3GL2. Meanwhile, the ERK and PI3K/AKT signaling pathways were significantly activated, leading to the decreased expression of apoptotic protein and increased expression of anti-apoptotic protein. Furthermore, in orthotopic mouse xenografts, the mice given stable over-expressed SH3GL2 cells co-transfected with miR-330 knockdown plasmid had the smallest tumor sizes and longest survival. In conclusion, these results suggested that miR-330 negatively regulated the expression of SH3GL2 in GSCs, which promoted the oncogenic progression of GSCs through activating ERK and PI3K/AKT signaling pathways. The elucidation of these mechanisms will provide potential therapeutic approaches for human glioblastoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Animals
Apoptosis / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases / metabolism*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glioblastoma / genetics*
Glioblastoma / metabolism*
Glioblastoma / mortality
Glioblastoma / pathology
Humans
Mice
MicroRNAs / genetics*
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Phosphatidylinositol 3-Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction*
Tumor Burden
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
MIRN330 microRNA, human
MicroRNAs
SH3GL2 protein, human
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases

Grants and funding

This work is supported by grants from the Natural Science Foundation of China (81172197, 81072056, 81171131, 81272564, 81272795 and 81372484), the special fund for Scientific Research of Doctor-degree Subjects in Colleges and Universities, (20102104110009), the Natural Science Foundation of Liaoning Province in China (No. 201102300), Liaoning Science and Technology Plan Projects (No. 2011225020), Shenyang Science and Technology Plan Projects (nos. F11-264-1-15, F12-277-1-05, F13-318-1-16 and F13-220-9-15), and Outstanding Scientific Fund of Shengjing Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.