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Huang C.,Central South University | Huang C.,Key Laboratory of Carcinogenesis and Cancer Invasion | Huang C.,Key Laboratory of Carcinogenesis | Huang C.,Peking University | And 20 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Purpose: To identify the novel gene signatures and molecular markers of nasopharyngeal carcinoma (NPC) by integrated bioinformatics analysis of multiple gene expression profiling datasets. Experimental Design: Seven published gene expression profiling studies and one of our unpublished works were reanalyzed to identify the common significantly dysregulated (CSD) genes in NPC. Overrepresentation analysis of cytogenetic bands, Gene Ontology (GO) categories, pathways were used to explore CSD genes functionally associated with carcinogenesis. The protein expressions of selected CSD genes were examined by immunohistochemistry on tissue microarrays, and the correlations of their expressions with clinical outcomes were evaluated. Results: Using the criteria (genes reported deregulated in more than one study), a total of 962 genes were identified as the CSD genes in NPC. Four upregulated (BUB1B, CCND2, CENPF, and MAD2L1) and two downregulated (LTF and SLPI) genes were markedly reported in six studies. The enrichments of chromosome aberrations were 2q23, 2q31, 7p15, 12q15, 12q22, 18q11, and 18q12 in upregulated genes and 14q32 and 16q13 in downregulated genes. The activated GO categories and pathways related to proliferation, adhesion, invasion, and downregulated immune response had been functionally associated with NPC. SLPI significantly downregulated in nasopharyngeal adenocarcinoma. Furthermore, the high expression of BUB1B or CENPF was associated with poor overall survival of patients. Conclusion: It was first clearly identified the dysregulated expression of BUB1B and SLPI in NPC tissues. Impact: Further studies of the CSD genes as gene signatures and molecular markers of NPC might improve the understanding of the disease and identify new therapeutic targets. ©2011 American Association for Cancer Research.

Yu Z.,Central South University | Liu Q.,Center for Skull Base Surgery and Neurooncology | Huang C.,Central South University | Huang C.,Peking University | And 3 more authors.
OMICS A Journal of Integrative Biology | Year: 2013

The aim of the present work was to perform a meta-analysis to evaluate the association between the interleukin 10 (IL-10)-819C/T (rs1800871) polymorphism and cancer risk. A total of 73 studies, including 15,942 cancer cases and 22,336 controls, were identified in this meta-analysis. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Overall, no significant association was identified between the IL-10-819C/T polymorphism and cancer risk. In the subgroup analyses, the T allele and TT genotype were associated with a moderately reduced cancer risk in the Asian population (T allele vs. C allele: OR=0.93, 95%CI: 0.87, 0.99; TT vs. CC: OR=0.86, 95%CI: 0.76, 0.98; TT vs. CT/CC: OR=0.90, 95%CI: 0.82, 0.98). Individuals who were homozygous for the T allele (TT) were found to be associated with significantly reduced gastric cancer risk in the Asian population. The heterozygous variant (CT) and the dominant model (TT/CT vs. CC) were associated with an increased risk for cervical and ovarian cancer. However, the IL-10-819C/T polymorphism was not significantly associated with breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, lymphoma, or melanoma. The depressed cancer risk of the TT genotype occurred in the studies of hospital-based case-control studies and the studies recruited less than 500 subjects, but no statistically significant results were found in the stratified analyses using genotyping method. The results suggest that the IL-10-819TT genotype may be a protective factor for cancer in Asians, especially gastric cancer. In contrast, the CT genotype and the dominant model could be risk factors for cervical and ovarian cancer. The importance of stratifying by ethnicity, cancer type, study design, and sample size needs to be standardized in future studies, together with considering the association between the IL-10-819C/T polymorphism and cancer risk. Furthermore, the linkage of-819C/T with other polymorphisms of the IL-10 gene may help explain the variability in findings. © 2013, Mary Ann Liebert, Inc.

Tang H.,Sun Yat Sen University | Liu Q.,Center for Skull Base Surgery and Neurooncology | Liu X.,Sun Yat Sen University | Ye F.,Sun Yat Sen University | And 2 more authors.
Journal of Cancer Research and Therapeutics | Year: 2015

Introduction: Specific microRNA (miRNA) expression signatures have been identified in a variety of human cancers. More recently, increasing evidence shows that miRNAs exist in human blood serum and plasma. Materials and Methods: Levels of miR-185 in plasma were measured by quantitative reverse-transcriptase polymerase chain reaction in 66 glioma patients, 11 pituitary adenoma patients, 32 meningioma patients, and 14 acoustic neuroma patients. Results: The plasma levels of miR-185 were significantly altered in glioma patients compared to normal controls. However, its levels were not observably changed in patients with other brain tumors such as meningioma, acoustic neuroma, or pituitary adenoma. Furthermore, the plasma levels of miR-185 in glioblastoma multiforme patients with operation and chemo-radiation almost revived to normal levels. Finally, we also demonstrated that low plasma miR-185 levels are correlated with poor survival in glioma patients. Conclusion: These findings suggest that plasma miR-185 has become potential biomarkers for glioma and may be useful in clinical management for glioma patients.

Tang H.,Central South University | Tang H.,Sun Yat Sen University | Wang Z.,Central South University | Liu Q.,Center for Skull Base Surgery and Neurooncology | And 5 more authors.
PLoS ONE | Year: 2014

Inactivated LRRC4 has been clinically detected in gliomas, and promoter hypermethylation has been implicated as the mechanism of inactivation in some of those tumors. Our previous researches indicated that LRRC4 is a target gene of miR- 381, the interaction of miR-381 and LRRC4 is involved in glioma growth. In this study, we demonstrate that LRRC4 is a target gene of the other microRNA, miR-182. We found that the high expression of miR-182 and miR-381 in gliomas are involved in pathological malignant progression. The silencing of miR-182 and miR-381 inhibited the proliferation in vitro and growth of glioma cell with in vivo magnetic resonance imaging by intracranial transplanted tumor model in rats. We also demonstrated that BRD7, a transcriptional cofactor for p53, is highly expressed and negatively correlated with LRRC4 expression in gliomas. Disturbing miR-182 and miR-381 affected transcriptional regulation of the BRD7 gene. This finding was verified by ectopic overexpression of LRRC4 or restoration of endogenous LRRC4 expression by treatment with the DNA demethylating agent 5-Aza-dC. Taken together, miR-182 and miR-381 may be a useful therapeutic target for treatment of glioma.© 2014 Tang.

Tang H.,Central South University | Tang H.,Center for Skull Base Surgery and Neurooncology | Tang H.,Key Laboratory of Carcinogenesis and Cancer Invasion | Biana Y.,Central South University | And 13 more authors.
Current Cancer Drug Targets | Year: 2013

Many microRNAs reside in clusters in the genome, are generally similar in sequence, are transcribed in the same direction, and usually function synergistically. The miR-183/96/182 cluster is composed of 3 miRNA genes, and increased expression of miR-183, 96 and 182 are implicated in glioma carcinogenesis. Knockdown of individual components or of the entire miR-183/96/182 cluster inhibits the survival of glioma cells by regulating the ROS-induced apoptosis pathway. Furthermore, inhibition of the miR-183/96/182 cluster induced ROS-mediated AKT/survival independent of three target genes FGF9, CPEB1, and FOXO1, and inhibition of the miRNA cluster induced p53/apoptosis signaling, which was dependent on these same genes. In addition, knockdown of the miR-183/96/182 cluster enhanced the anticancer effect of Temozolomide on glioma cells by the ROS-mediated apoptosis pathway. Therefore, the miR- 183/96/182 cluster may be a pleiotropic target for glioma therapy. © 2013 Bentham Science Publishers.

Xiaoping L.,Central South University | Xiaoping L.,Key Laboratory of Carcinogenesis and Cancer Invasion | Xiaoping L.,Key Laboratory of Carcinogenesis | Xiaoping L.,Center for Skull Base Surgery and Neurooncology | And 29 more authors.
Cell Death and Disease | Year: 2013

Epigenetic mechanisms have important roles in carcinogenesis. We certified that the mRNA translation-related gene cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is hypomethylated and overexpressed in glioma cells and tissues. The knockdown of CPEB1 reduced cell senescence by regulating the expression or distribution of p53 in glioma cells. CPEB1 is also regulated directly by the tumor suppressor miR-101, a potential marker of glioma. It is known that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) and embryonic ectoderm development (EED) are direct targets of miR-101. We demonstrated that miR-101 downregulated the expression of CPEB1 through reversing the methylation status of the CPEB1 promoter by regulating the presence on the promoter of the methylation-related histones H3K4me2, H3K27me3, H3K9me3 and H4K20me3. The epigenetic regulation of H3K27me3 on CPEB1 promoter is mediated by EZH2 and EED. EZH2 has a role in the regulation of H3K4me2. Furthermore, the downregulation of CPEB1 induced senescence in a p53-dependent manner. © 2013 Macmillan Publishers Limited All rights reserved.

Xiao L.,Central South University | Xiao L.,Key Laboratory of Carcinogenesis and Cancer Invasion | Xiao L.,Key Laboratory of Carcinogenesis | Xiao L.,Center for Skull Base Surgery and Neurooncology | And 27 more authors.
Medical Oncology | Year: 2014

Pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations such as GNAS, MEN1, CNC, and FIPA. LRRC4 is relatively tissue-specific expressed gene in the normal brain and downregulated expression in glioma (87.5 %), meningioma (80.9 %), and pituitary adenoma (85.5 %). It has been suggested that the aberrant expression of LRRC4 contributes to tumorigenesis in glioma. However, little is known yet about association between LRRC4 and risk of pituitary adenoma. In this study, we genotyped three LRRC4 haplotype-tagging SNPs (htSNP) by direct sequencing in case-control studies, which included 183 Han Chinese patients diagnosed with pituitary adenoma and 183 age-, gender-matched, and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNP. We observed statistically significant differences regarding the genotype TT + CT of rs6944446 in the NCA. Haplotype AC of rs3823994-rs6944446 is suggested to have a protective effect in the development of pituitary adenoma (OR 0.339; 95 % CI 0.123-0.934). However, haplotype GT of rs3808058-rs6944446 (OR 1.575; 95 % CI 1.048-2.368) and AGT of rs3823994-rs6944446-rs3808058 (OR 1.673; 95 % CI 1.056-2.651) might be a risk factor for pituitary adenoma development. In a brief, the results support the hypothesis that polymorphisms or haplotypes in the LRRC4 may have important research significance and could be used to predict the risk of pituitary adenoma. © 2014 Springer Science+Business Media New York.

She X.,Central South University | Yu Z.,Central South University | Yu Z.,Center for Skull Base Surgery and Neurooncology | Cui Y.,Central South University | And 10 more authors.
Oncology Reports | Year: 2014

Glioblastoma multiforme (GBM) is one of the most deadly diseases affecting humans, and is often characterized by poor survival and by high resistance to chemotherapy and radiotherapy. Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of GBM following surgery. Although TMZ may restrain GBM growth, TMZ resistance is also common and accounts for numerous cases of treatment failure. Studies indicate that aberrant miRNA expression is associated with hallmark malignant properties of GBM. Thus, miRNA-based anticancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies to enhance the efficacy of chemotherapy agents. In the present study, we demonstrated that the expression of miR-128 and miR-149 was downregulated in glioblastoma, and their overexpression inhibited the invasion of glioblastoma cells by targeting Rap1B-mediated cytoskeletal and related molecular alterations. Moreover, miR-128 and miR-149 enhanced the chemosensitivity of glioblastoma cells to TMZ.

She X.,Central South University | She X.,Key Laboratory of Carcinogenesis | Yu Z.,Central South University | Yu Z.,Key Laboratory of Carcinogenesis | And 17 more authors.
Medical Oncology | Year: 2014

Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Although chemotherapy with temozolomide (TMZ) may restrain tumor growth for some months, TMZ resistance is also common and accounts for many treatment failures. Research into microRNA's role in GBM has shown that microRNAs play a key regulatory role in the GBM, making it a potential therapeutic target. In this study, we demonstrated that the lower expression of miR-181a/b/c/d subunits contributes to astrocytoma tumorigenesis, and their overexpression could inhibit the invasive proliferation of glioblastoma cells by targeting Rap1B-mediated cytoskeleton remodeling and related molecular (Cdc42, RhoA and N-cadherin) changes, suggesting that miR-181 was a critical regulator and might be an important target for glioblastoma treatment. TMZ as a standard chemotherapeutic agent for GBM inhibited the Rap1B expression and actin cytoskeleton remodeling to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma cells. © 2014 Springer Science+Business Media New York.

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