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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.


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.


Shi Z.-D.,Tianjin Medical University | Shi Z.-D.,Key Laboratory of Neurotrauma | Qian X.-M.,Tianjin University | Liu C.-Y.,Tianjin University | And 13 more authors.
CNS Neuroscience and Therapeutics | Year: 2013

Background and Aims: Currently temozolomide (TMZ) as a potent agent is widely used to treat the glioblastoma multiforme (GBM), whereas recurrence due to intrinsic or acquired therapeutic resistance often occurs. Combination chemotherapy with TMZ may be a promising therapeutic strategy to improve treatment efficacy. Methods: Aspirin, TMZ, and aspirin-/TMZ-coloaded poly (L-lactide-co-glycolide) (PLGA) microspheres were prepared by spray drying, and cytotoxicities of glioblastoma cells were measured. Results: Aspirin microsphere treatment induced slight apoptosis and modestly inhibited proliferation of LN229 and U87 cells in vitro and in vivo through inhibition of β-catenin transactivation. However, aspirin-/TMZ-coloaded microspheres presented synergistic antitumor efficacy compared with single TMZ-loaded microspheres. Aspirin/TMZ microspheres induced more apoptosis and repressed proliferation of LN229 and U87 cells. Corresponding to inhibition of β-catenin signaling, β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity were strongly suppressed, and downstream targets expression was decreased. Furthermore, aspirin/TMZ microsphere intratumoral injection downregulated the expression of β-catenin, TCF4, pAKT, pSTAT3, and PCNA and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts. Conclusions: Aspirin sensitized TMZ chemotherapy efficacy through inhibition of β-catenin transactivation; furthermore, the coloaded microspheres achieved a sustained release action to reduce the TMZ dosage, offering the potential for improved treatment of glioblastomas. © 2012 Blackwell Publishing Ltd.


Zhang C.,Tianjin Medical University | Zhang C.,Key Laboratory of Neurotrauma | Zhang C.,Tianjin Huanhu Hospital | Zhang J.,Tianjin Medical University | And 10 more authors.
International Journal of Oncology | Year: 2010

miR-221 and miR-222 (miR-221/222) are frequently up-regulated in human epithelial cancers. However, the mechanism of miR-221/222 action involved in carcinogenesis has not been extensively studied. Here, we found that reduction of miR-221/222 inhibited cell proliferation and induced mitochondrial-mediated apoptosis in human epithelial cancer cells (A549 lung cancer and MCF-7 breast cancer cells). Bioinformatics and luciferase reporter assays showed that miR-221/222 co-modulated the p53 up-regulated modulator of apoptosis (PUMA) expression by directly targeting the binding site within the 3'UTR. Together, these findings suggest that PUMA is a direct target of miR-221/222 that functions as an endogenous apoptosis regulator in these epithelial cancers.


Chen L.,Tianjin Medical University | Chen L.,Key Laboratory of Neurotrauma | Chen L.,Harbin Medical University | Chen L.,Fudan University | And 19 more authors.
Cancer Letters | Year: 2013

MicroRNAs are strongly implicated as affecting glioma, but their specific roles and functions have yet to be fully elucidated. In this study, we defined the expression and function of miR-24, which we found to be upregulated in glioma samples and glioma cells by qRT-PCR. Downregulation of miR-24 in glioma cell lines inhibited proliferation and invasion and induced apoptosis. Using computational and expression analysis, ST7L was identified as a candidate target of miR-24. A reporter assay with the 3'UTR of ST7L cloned downstream of a luciferase gene showed increased luciferase activity in the absence of miR-24, providing strong evidence that miR-24 is a direct regulator of ST7L. Furthermore, we observed that restoration of ST7L activity resulted in effects that were similar to those from transfecting a miR-24 inhibitor into glioma cells. Mechanistic investigation revealed that the deletion of miR-24 suppressed β-catenin/Tcf-4 transcription activity by targeting ST7L. In conclusion, our study demonstrates that miR-24 upregulation is common in glioma and that suppression of miR-24 expression inhibits cell proliferation and invasion, suggesting that miR-24 may act as an oncogene in glioma. © 2012 Elsevier Ireland Ltd.


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.


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 | Han L.,Tianjin Medical University | Han L.,Key Laboratory of Neurotrauma | Zhang K.,Tianjin Medical University | And 16 more authors.
Neuro-Oncology | Year: 2012

Aberrant microRNA expression has been implicated in the development of human cancers. Here, we investigated the oncogenic significance and function of miR-23b in glioma. We identified that the expression of miR-23b was elevated in both glioma samples and glioma cells, indicated by real-time polymerase chain reaction analyses. Down-regulation of miR-23b triggered growth inhibition, induced apoptosis, and suppressed invasion of glioma in vitro. Luciferase assay and Western blot analysis revealed that VHL is a direct target of miR-23b. Restoring expression of VHL inhibited glioma proliferation and invasion. Mechanistic investigation revealed that miR-23b deletion decreased HIF-1α/VEGF expression and suppressed β-catenin/Tcf-4 transcription activity by targeting VHL. Furthermore, expression of VHL was inversely correlated with miR-23b in glioma samples and was predictive of patient survival in a retrospective analysis. Therefore, we demonstrated that downregulation of miR-23b suppressed tumor survival through targeting VHL, leading to the inhibition of β-catenin/Tcf-4 and HIF-1α/VEGF signaling pathways. © The Author(s) 2012.


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.


Tian Y.,Tianjin Medical University | Tian Y.,Tianjin Neurological Institute | Tian Y.,Key Laboratory of Neurotrauma | Nan Y.,Tianjin Medical University | And 20 more authors.
International Journal of Oncology | Year: 2012

The microRNA miR-451 is downregulated in gliomas, this has been suggested by several different research groups and is consistent with our data. Our previous study also confirmed that miR-451 has a repressive role in glioma by inhibiting cell growth, proliferation and by inducing cell apoptosis. In the present study, we identified a target gene of miR-451 in human glioma and investigated the mechanism for the glioma suppressive effect of miR-451 functions. Expression of miR-451 in gliomas was identified by quantitative real-time PCR and fluorescence in situ hybridization. Human glioma cell lines (U251, U87, LN229 and A172) were transfected with miR-451 mimics to restore miR-451 expression. The tumor suppressive effects of miR-451 were further verified by subcutaneous assays in nude mice, in addition to our previous in vitro data. A candidate target gene was tested by Western blotting and luciferase reporter assays. Some PI3K/AKT pathway factors were tested by Western blotting. We found that miR-451 expression was downregulated in glioma samples and was inversely correlated with WHO grades of gliomas. In vivo assays confirmed that miR-451 had tumor suppressive traits. CAB39-3'UTR lucife-rase reporter assay confirmed CAB39 as a direct target gene of miR-451. Significant alterations in the expression of PI3K/AKT pathway factors were observed by Western blot assays. We conclude that miR-451 represses glioma in vitro and in vivo, likely through targeting CAB39 directly and inhibiting the PI3K/AKT pathway indirectly.

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