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Silencing microRNA‐221/222 cluster suppresses glioblastoma angiogenesis by suppressor of cytokine signaling‐3‐dependent JAK/STAT pathway
Author(s) -
Xu ChunHua,
Liu Yue,
Xiao LiMin,
Chen LiKe,
Zheng SuYue,
Zeng ErMing,
Li DongHai,
Li YouPing
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28794
Subject(s) - stat , suppressor of cytokine signaling 1 , jak stat signaling pathway , gene silencing , socs3 , angiogenesis , suppressor of cytokine signalling , microrna , cytokine , cancer research , suppressor , signal transduction , socs6 , microbiology and biotechnology , stat3 , biology , immunology , genetics , tyrosine kinase , gene
Angiogenesis is a major pathologic characteristic of glioblastoma, which is one aggressive primary brain tumor. MicroRNA‐221/222 (miR‐221/222) cluster has been previously reported to function importantly in malignant glioma biological process. The current study aims at evaluating the effects of miR‐221/222 cluster on angiogenesis of glioblastoma cells. Microarray data were analyzed to select glioblastoma‐associated differentially expressed genes, and dual‐luciferase reporter assay was performed to assess targeting correlation between miR‐221/222 cluster and suppressor of cytokine signaling‐3 (SOCS3). Subsequently, the expression patterns of miR‐221 and miR‐222 in glioblastoma cells were identified. miR‐221 and miR‐222 were overexpressed or silenced in glioblastoma cells to identify the effect of miR‐221/222 cluster in cell invasion, migration, proliferation, and angiogenesis. To define downstream pathway of miR‐221/222 cluster or SOCS3 in glioblastoma, levels of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway‐related proteins were assessed. Additionally, the functions of miR‐221/222 on glioblastoma cell angiogenesis were measured in vivo with microvessel density assayed. miR‐221 and miR‐222 were expressed at a high level and SOCS3 was at a low level in glioblastoma. Downregulation of the miR‐221/222 cluster diminished the invasion, migration, proliferation, and angiogenesis with reduced protein levels of matrix metalloproteinase‐2 (MMP‐2), MMP‐9, and vascular endothelial growth factor in glioblastoma cells. Also, silencing miR‐221/222 cluster reduced p‐JAK2/JAK2 and p‐STAT3/STAT3. Consistently, the inhibitory role of silencing miR‐221/222 cluster on tumorigenesis of glioblastoma cells was confirmed in vivo. Collectively, the inhibition of miR‐221/222 cluster could attenuate the glioblastoma angiogenesis through inactivation of the JAK/STAT pathway by upregulating SOCS3.