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Tang Y.,Soochow University of China | Cui Y.,Anhui Provincial Hospital | Li Z.,State Oceanic Administration | Jiao Z.,Changzhou University | And 8 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2016

Background: Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses. Methods: In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism. Results: Nine miRNAs, including miR-29b-3p, miR-200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR-208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects. Conclusions: The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients. © 2016 Tang et al. Source


Fan S.-H.,Jiangsu University | Wang Y.-Y.,First Peoples Hospital of Xuzhou | Lu J.,Jiangsu University | Zheng Y.-L.,Jiangsu University | And 6 more authors.
Journal of Cellular Biochemistry | Year: 2015

Ceramide synthase 2 (CERS2) is the gene identified from a human liver cDNA library in 2001. Our previous studies have shown higher expression of CERS2 in the breast cancer patients was associated with fewer lymph node metastases. However, the molecular mechanism of CERS2 involved is unknown. Here, we found CERS2 was heterogeneously expressed in various breast cancer cells. The mRNA and protein expression levels of CERS2 in MCF7 cells, which are poorly invasive breast cancer cells, were obviously higher than that in the highly invasive cells MDA-MB-231. Results showed overexpression of CERS2 in MDA-MB-231 cells could significantly inhibit the migration and invasion ability, whereas CERS2 knockdown in MCF7 cells could significantly increase the migration and invasion ability. Overexpression of CERS2 in MDA-MB-231 cells significantly reduced the V-ATPase activity, increased the extracellular pH and decreased the pH-dependent activity of MMP-2 and MMP-9 matrix metalloproteinases (MMPs). CERS2 knockdown in MCF7 cells significantly increased the V-ATPase activity, decreased the extracellular pH and increased the activity of MMP-2 and MMP-9. Taken together, CERS2 can significantly inhibit breast cancer cell invasion and is associated with the decrease of the V-ATPase activity and extracellular hydrogen ion concentration, and in turn the activation of secreted MMP-2/MMP-9 and degradation of extracellular matrix (ECM), which ultimately suppressed tumor's invasion. Thus, CERS2 may represent a novel target for selectively disrupting V-ATPase activity and the invasive potential of cancer cells. J. Cell. Biochem. 116: 502-513, 2015. © 2014 Wiley Periodicals, Inc. Source


Wang Z.L.,Nanjing Medical University | Tang Z.C.,Nanjing Medical University | Zhang Y.,First Peoples Hospital of Xuzhou | Zhang W.,Nanjing Medical University | And 5 more authors.
Head and Neck Oncology | Year: 2012

Objective Our previous study demonstrated that neuropilin-1 is useful for the prognosis of tongue squamous cell carcinoma. In this study, we aimed to explore the role of neuropilin-1 in the differentiation of tongue squamous cell carcinoma. Methods Forty primary tongue squamous cell carcinoma samples were subjected to immunostaining for neuropilin-1. The relationship between neuropilin- 1 expression and differentiation was analysed. A specific small hairpin ribonucleic acid (shRNA) targeting neuropilin-1 was transfected into the tongue squamous cell carcinoma cell line squamous cell carcinoma-25 to knockdown neuropilin-1 expression. Scratch and transwell assays were performed to examine the cell migration and invasion ability after neuropilin- 1 was knockeddown. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot were used to detect the efficiency of neuropilin-1 knockdown and the expression of differentiation markers. Results We found a significant correlation between the high neuropilin-1 expression level and the poor histopathological differentiation of tongue squamous cell carcinoma (p = 0.026). Neuropilin-1 was expressed at a high level in squamous cell carcinoma-25 cells. After neuropilin-1 knockdown via shRNA, cell migration and invasion were significantly reduced as demonstrated by scratch and transwell assays (p < 0.01). In addition, Western blotting and RT-PCR demonstrated that neuropilin-1 knockdown increased E-cadherin and decreased fibronectin and vimentin expression in squamous cell carcinoma-25 cells. Conclusion Neuropilin-1 knockdown may inhibit the migration and invasion of tongue squamous cell carcinoma by inducing a more differentiated cancer state. Considering the high level of neuropilin- 1 expression in tongue squamous cell carcinoma, it may serve as a useful marker for differentiation and as a target for the treatment of tongue cancer. Copyright © 2012 OA Publishing London. Source


Fan S.-H.,Jiangsu University | Wang Y.-Y.,First Peoples Hospital of Xuzhou | Lu J.,Jiangsu University | Zheng Y.-L.,Jiangsu University | And 6 more authors.
PLoS ONE | Year: 2014

The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC. © 2014 Fan et al. Source


Yuan G.,Jiangsu University | Hu H.,Jiangsu University | Wang S.,Jiangsu University | Yang Q.,Jiangsu University | And 9 more authors.
Endocrine Journal | Year: 2015

Glycemic variability (GV) has been proposed as contributor to diabetes-related macrovascular complications. This randomized control trial evaluated a new combination therapy with continuous subcutaneous insulin infusion (CSII) plus sitagliptin (CSII + sitagliptin) vs. CSII only in terms of metabolic control, GV and β-cell function in patients with newly diagnosed type 2 diabetes (T2DM). 217 patients were randomized to two weeks of CSII (n = 108) or CSII + sitagliptin (n = 109) therapy. As a measure of GV, the coefficient of variation (CV) was computed from capillary blood glucose during the first and second week, respectively. β-cell function before and after treatment was determined with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). Good metabolic controls were established with both therapies. CSII + sitagliptin therapy resulted in greater improvements in CV and ISSI-2 than CSII alone (all P = 0.000). For each group, change in CV was inversely correlated with change in ISSI-2 (r = -0.529, P = 0.000 and r = -0.433, P = 0.000, respectively). The multivariate regression analysis demonstrated that improved ISSI-2 was the only independent contributor to reduced CV in both groups (standardized β = -0.388, P = 0.004 and standardized β = -0.472, P = 0.000, respectively). Correction of β-cell function in newly diagnosed T2DM patients via use of either CSII or CSII + sitagliptin therapy was feasible in controlling GV to prevent secondary complications of T2DM. Moreover, CSII + sitagliptin therapy was superior to CSII monotherapy in terms of GV. © The Japan Endocrine Society. Source

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