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Shi Y.,Huazhong University of Science and Technology | Shi Y.,Shanghai Genome Pilot Institutes for Genomics and Human Health | Shi Y.,Changning Mental Health Center | Li L.,Guangxi Province Tumor Hospital | And 86 more authors.
Nature Genetics | Year: 2013

To identify new genetic risk factors for cervical cancer, we conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched = 9.69 × 10-9, per-allele odds ratio (OR)stringently matched = 1.26) and 17q12 (rs8067378, Pcombined, stringently matched = 2.00 × 10-8, per-allele ORstringently matched = 1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched = 4.52 × 10-27, per-allele ORstringently matched = 0.75). Our findings provide new insights into the genetic etiology of cervical cancer. © 2013 Nature America, Inc. All rights reserved.

Liu G.,Wuhan University | Liu G.,Taihe Hospital of Shiyan | Yuan Y.,Wuhan University | Liu Y.,Wuhan University | Zhou X.,Wuhan University
Medical Journal of Wuhan University | Year: 2012

Objective: To study the effect of RNA interference of insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) receptors on biological features and radioactivity of NPC cells. Methods: The IGF-1R and EGFR target RNAi eukaryotic expression plasmids labeled with fluorescence and transfect the nasopharyngeal cells (CNE-2) were constructed. The transfection efficiency was tested by the laser confocal microscopy. The survival fraction was investigated by cell colony formation after irradiation. The cell cycles and apoptosis were determined via flow cytometry. The cyclins (cdk4/6, cyclin D1 and c-myc) expressions were assessed by Western blot. Results: The eukaryotic expression plasmid was successfully constructed. Compared with the control group, the siRNA-IGF-1R & EGFR group showed significantly decreased survival fraction (P < 0.05), increased apoptosis and G 0/G 1 cell ratio (P < 0.05) , and detreased cell ratio of S stage and G 2/M. The Western-blot results showed that the cdk4/6, cyclin D1, and c-myc expression significantly decreased (P < 0.05). Conclusion: The dual-silencing of IGF-1R and EGFR are capable of decreasing expression of NPC cyclins and blocking cell cycles, which can promote the apoptosis.

Xu C.-S.,Wuhan University | Wang Z.-F.,Wuhan University | Huang X.-D.,Wuhan University | Huang X.-D.,Taihe Hospital of Shiyan | And 3 more authors.
Journal of Translational Medicine | Year: 2015

Background: Melatonin, a well-known antioxidant, has been shown to possess anti-invasive properties for glioma. However, little is known about the effect of melatonin on glioma cell migration and invasion under hypoxia, which is a crucial microenvironment for tumor progress. In addition, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration and invasion. Therefore, we investigated the possible role of these kinases and its related signaling in the regulation of human U251 glioma cells behavior by melatonin under hypoxia. Methods: The abilities of migration and invasion of U251 glioma cells were determined by wound healing and transwell assay in vitro. The intracellular production of reactive oxygen species (ROS) was measured by using the fluorescent probe 6-carboxy-2', 7'-dichorodihydrofluorescein diacetate (DCFH-DA). Immunofluorescence experiments and western blotting analysis were used to detect the expression level of protein. Small interfering RNAs (siRNA) was used to silence specific gene expression. Results: The pharmacologic concentration (1 mM) of melatonin significantly inhibited the migration and invasion of human U251 glioma cells under hypoxia. The inhibitory effect of melatonin was accompanied with the reduced phosphorylation of FAK and Pyk2, and decreased expression of alpha v beta 3 (αvβ3) integrin. Additionally, inhibition of αvβ3 integrin by siRNA reduced the phosphorylation of FAK/Pyk2 and demonstrated the similar anti-tumor effects as melatonin, suggesting the involvement of αvβ3 integrin- FAK/Pyk2 pathway in the anti-migratory and anti-invasive effect of melatonin. It was also found that melatonin treatment decreased the ROS levels in U251 glioma cells cultured under hypoxia. ROS inhibitor apocynin not only inhibited αvβ3 integrin expression and the phosphorylation levels of FAK and Pyk2, but also suppressed the migratory and invasive capacity of U251 glioma cells under hypoxia. Conclusions: These results suggest that melatonin exerts anti-migratory and anti-invasive effects on glioma cells in response to hypoxia via ROS-αvβ3 integrin-FAK/Pyk2 signaling pathways. This provides evidence that melatonin may be a potential therapeutic molecule targeting the hypoxic microenvironment of glioma. © Xu et al.

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