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Zhu-Mei Shi,
Xie-Feng Wang,
Xu Qian,
Tao Tao,
Lin Wang,
Qiu-Dan Chen,
Xi-Rui Wang,
Lei Cao,
Ying-Yi Wang,
Jun-Xia Zhang, Tao Jiang,
Chun-Sheng Kang,
Bing-Hua Jiang,
Ning Liu,
Yong-Ping You
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ABSTRACT: MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.
RNA 02/2013; · 5.09 Impact Factor
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Jun-Xia Zhang,
Jing Zhang,
Wei Yan,
Ying-Yi Wang,
Lei Han,
Xiao Yue,
Ning Liu,
Yong-Ping You, Tao Jiang,
Pei-Yu Pu,
Chun-Sheng Kang
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ABSTRACT: Background
Aberrant activation of beta-catenin/TCF4 and STAT3 signaling in glioblastoma multiforme (GBM) has been reported. However, the molecular mechanisms related to this process are still poorly understood.Methods
Genome-wide screening of the binding characteristics of the transcription factors TCF4 and STAT3 in GBM cells was performed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the association of TCF4 and STAT3 coregulated genes with The Cancer Genome Atlas (TCGA) GBM subtypes (classical, mesenchymal, neural, and proneural). New molecular classification of GBM was proposed and validated in Western and Asian populations.ResultsWe identified 1250 overlapping putative target genes that were coregulated by TCF4 and STAT3. Further, the coregulated genes had the potential to guide TCGA GBM subtypes. Finally, we proposed a new molecular classification of GBM into 2 subtypes (proneural-like and mesenchymal-like) and showed that the new classification could be applied to both Western and Asian populations. In addition, the GBM response to temozolomide therapy differed depending on its subtype; mesenchymal-like GBM benefited, while there was no benefit for proneural-like GBM.Conclusions
This is the first comprehensive study to combine a ChIP-seq assay of TCF4 and STAT3 and data mining of patient cohorts to derive molecular subtypes of GBM.
Neuro-Oncology 01/2013; · 5.72 Impact Factor
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Lei Han,
Xiao Yue,
Xuan Zhou,
Feng-Ming Lan,
Gan You,
Wei Zhang,
Kai-Liang Zhang,
Chun-Zhi Zhang,
Jin-Quan Cheng,
Shi-Zhu Yu,
Pei-Yu Pu, Tao Jiang,
Chun-Sheng Kang
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ABSTRACT: MicroRNA-21 (miR-21) expression is increased in many types of human malignancy, including glioma. Recent studies report that miR-21 regulates cell invasion by targeting RECK, however, the underlying transcriptional regulation of miR-21 in glioma cells remains elusive.
Here, we identify a positive correlation between miR-21 expression and pathological grade in glioma tissues. We demonstrate that β-catenin pathway regulates miR-21 expression in human umbilical vein endothelial cell and glioma cells, and that this regulation is signal transducer and activator of transcription 3 (STAT3)-dependent. Further, chromatin immunoprecipitation and luciferase reporter analysis demonstrate that miR-21 is controlled by an upstream promoter containing a conserved STAT3 binding site. Notably, knockdown of miR-21-inhibited cell invasion by increasing RECK expression and decreased tumor growth in a xenograft model.
These data provide compelling evidence that β-catenin regulation of miR-21 via STAT3 plays a role in glioma cell invasion and proliferation and indicate that STAT3 is a potential therapeutic target for glioma intervention.
CNS Neuroscience & Therapeutics 05/2012; 18(7):573-83. · 4.44 Impact Factor
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Xie-Feng Wang,
Zhu-Mei Shi,
Xi-Rui Wang,
Lei Cao,
Ying-Yi Wang,
Jun-Xia Zhang,
Yu Yin,
Hui Luo,
Chun-Sheng Kang,
Ning Liu, Tao Jiang,
Yong-Ping You
[show abstract]
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ABSTRACT: Recently, several microRNAs (miRNAs) were reported to be involved in the modulation of glioma development. The aim of our study was to determine the effect of miR-181d on the growth of glioma and to investigate whether this growth is modulated by targeting K-ras and Bcl-2.
Real-time PCR was used to analyze the expression of miR-181d in human glioma samples and glioma cell lines. Apoptosis, cell cycle, and proliferation (MTT) assays were performed to assess the phenotypic changes in glioma cells. Immunohistochemistry was used to determine the expression of K-ras and Bcl-2 in glioma tissues, and a luciferase reporter assay was carried out to confirm whether K-ras and Bcl-2 are direct targets of miR-181d. Western blotting was used to identify the potential signaling pathways affected glioma cell growth by miR-181d. In vivo, xenograft tumors were examined for an anti-glioma effect of miR-181d.
MiR-181d was down-regulated in human glioma samples and up-regulated in transfected glioma cells. Ectopic expression of miR-181d suppressed proliferation and triggered cell cycle arrest and apoptosis in glioma cell lines. K-ras and Bcl-2 were identified as direct targets of miR-181d and were up-regulated in glioma samples. The results showed evidence linking the tumor suppressor activity of miR-181d in glioma cells with the K-ras-related PI3K/AKT and MAPK/ERK pathways. Furthermore, xenograft tumors from miR-181d-treated U251 cells were suppressed in vivo.
MiR-181d may act as a glioma suppressor by targeting K-ras and Bcl-2.
Journal of Cancer Research and Clinical Oncology 12/2011; 138(4):573-84. · 2.56 Impact Factor
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ABSTRACT: β-catenin, a key factor in the Wnt signaling pathway, has essential functions in the regulation of cell growth and differentiation. Aberrant β-catenin signaling has been linked to various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of the Wnt signaling pathway as it relates to β-catenin signaling in tumorigenesis, with particular focus on the role of microRNAs. Finally, we discuss the potential of β-catenin targeted therapeutics for cancer treatment.
Molecular Cancer 01/2010; 9:252. · 3.99 Impact Factor
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Chun-Zhi Zhang,
Jun-Xia Zhang,
An-Ling Zhang,
Zhen-Dong Shi,
Lei Han,
Zhi-Fan Jia,
Wei-Dong Yang,
Guang-Xiu Wang, Tao Jiang,
Yong-Ping You,
Pei-Yu Pu,
Jin-Quan Cheng,
Chun-Sheng Kang
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ABSTRACT: MiR-221 and miR-222 (miR-221/222) are frequently up-regulated in various types of human malignancy including glioblastoma. Recent studies have reported that miR-221/222 regulate cell growth and cell cycle progression by targeting p27 and p57. However the underlying mechanism involved in cell survival modulation of miR-221/222 remains elusive.
Here we showed that miR-221/222 inhibited cell apoptosis by targeting pro-apoptotic gene PUMA in human glioma cells. Enforced expression of miR-22/222 induced cell survival whereas knockdown of miR-221/222 rendered cells to apoptosis. Further, miR-221/222 reduced PUMA protein levels by targeting PUMA-3'UTR. Introducing PUMA cDNA without 3'UTR abrogated miR-221/222-induced cell survival. Notably, knockdown of miR-221/222 induces PUMA expression and cell apoptosis and considerably decreases tumor growth in xenograft model. Finally, there was an inverse relationship between PUMA and miR-221/222 expression in glioma tissues.
To our knowledge, these data indicate for the first time that miR-221/222 directly regulate apoptosis by targeting PUMA in glioblastoma and that miR-221/222 could be potential therapeutic targets for glioblastoma intervention.
Molecular Cancer 01/2010; 9:229. · 3.99 Impact Factor
