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Chen L.,Harbin Medical University | Zhang J.,Harbin Medical University | Feng Y.,Harbin Medical University | Li R.,Harbin Medical University | And 12 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2012

MET, the receptor for hepatocyte growth factor receptor (HGF), has been reported to trigger multiple and sometimes opposing cellular responses in various types of tumor cells. It has been implicated in the regulation of tumor-cell survival, proliferation, angiogenesis, invasion and metastasis. However, the MET regulatory mechanism in glioma is not well known. MicroRNAs are a class of small noncoding RNAs that play important roles in a variety of biological processes including human cancers. In this study, we used computational and expressional analysis to identify that the 'seed sequence' of miR-410 matched the 3′ UTR of the MET mRNA. Besides, the expression of miR-410 was inversely associated with MET in human glioma tissues. Using luciferase and western blot assay, we certified that miR-410 directly targeted MET in glioma cells. While restoring expression of miR-410 led to proliferation inhibition and reduced invasive capability in glioma cells. Furthermore, we showed that miR-410 played an important role in regulating MET-induced AKT signal transduction. While downregulation of MET by RNAi, we observed that MET knockdown resulted in effects similar to that with miR-410 transfection in glioma cells. Our findings suggest that miR-410, a direct regulator of MET, may function as a tumor suppressor in human gliomas.

Chen L.,Harbin Medical University | Zhang J.,Tianjin Medical University | Zhang J.,Key Laboratory of Neurotrauma | Han L.,Tianjin Medical University | And 13 more authors.
Oncology Reports | Year: 2012

A previous study showed that miR-221/222 can regulate cell apoptosis. p53 is a well known tumor suppressor which can influence the chemosensitivity of glioma cells. However, the effect of miR-221/222 in gliomas with different p53 status is unknown. Here, we demostrate that knockdown of miR-221/222 increases apoptosis in human gliomas of different p53 types (U251 cells, p53 mutant-type; LN308 cells, p53 null-type; and U87 cells, p53 wild-type). Furthermore, the effect of miR-221/22 caused no change of p53 expression in the glioma cells studied. In addition, when a specific siRNA against p53 was employed in U87 cells, no attenuation of apoptosis was found after knockdown of miR-221/222. Importantly, we found that As-miR-221/222-treated cells increased expression of Bax, cytochrome c, Apaf-1 and cleaved-caspase-3. Our results showed that low expression of miR-221/222 sensitized glioma cells to temozolomide (TMZ); in addition, ectopic expression of PUMA by pcDNA-PUMA had a similar effect. Taken together, our study indicates that downregulated miR-221/222 can sensitize glioma cells to TMZ by regulating apoptosis independently of p53 status.

Shi Z.,Tianjin Medical University | Shi Z.,Key Laboratory of Neurotrauma | Shi Z.,Chinese Glioma Cooperative Group CGCG | Zhang J.,Tianjin Medical University | And 25 more authors.
Cancer Research | Year: 2013

The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug. ©2013 AACR.

Chen L.,Harbin Medical University | Huang K.,Tianjin Medical University | Huang K.,Key Laboratory of Neurotrauma | Han L.,Tianjin Medical University | And 10 more authors.
International Journal of Oncology | Year: 2011

Increasing evidence suggests that interplays between Wnt/β-catenin and PI3K/AKT signaling cascades are involved in tumor development and progression. However, the exact mechanism in glioma is not well known. Using aspirin, we found that the expression levels of AKT1 in glioma cells significantly correlated with the transcriptional activity of β-catenin. Similar observations were made when we subjected glioma cells to treatment with Tcf4 siRNA. Moreover, both aspirin and Tcf4 siRNA can suppress the proliferation and induce apoptosis of glioma. In addition, our analysis of the gene promoter of AKT1 revealed multiple putative Tcf-4 binding sites. In support of the concept that β-catenin/Tcf-4 is a transcriptional regulator for AKT1, results from our chromatin immunoprecipitation studies and luciferase assay showed that β-catenin/Tcf-4 binds to the potential binding sites in the gene promoter of AKT1. Furthermore, using immunohistochemistry, we found that Tcf-4 protein expression increased significantly in high-grade glioma in comparison to low-grade glioma and correlated with AKT1 expression. In conclusion, our results support the concept that β-catenin/Tcf-4 directly regulates AKT1 in glioma, and these two proteins may cooperate with each other in exerting their oncogenic effects in glioma.

Duan R.,Capital Medical University | Duan R.,Chinese Glioma Cooperative Group CGCG | Han L.,Tianjin Neurological Institute | Han L.,Tianjin Medical University | And 24 more authors.
Oncotarget | Year: 2015

Homeobox (HOX) genes, including HOXA13, are involved in human cancer. We found that HOXA13 expression was associated with glioma grade and prognosis. Bioinformatics analysis revealed that most of the HOXA13-associated genes were enriched in cancer-related signaling pathways and mainly involved in the regulation of transcription. We transfected four glioma cell lines with Lenti-si HOXA13. HOXA13 increased cell proliferation and invasion and inhibited apoptosis. HOXA13 decreased β-catenin, phospho-smad2, and phospho-smad3 in the nucleus and increased phospho-β-catenin in the cytoplasm. Furthermore, downregulation of HOXA13 in orthotopic tumors decreased tumor growth. We suggest that HOXA13 promotes glioma progression in part via Wnt-and TGF-β-induced EMT and is a potential diagnostic biomarker for glioblastoma and an independent prognostic factor in highgrade glioma.

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