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The screening and analysis of protein signatures and signaling associated with chemoresistance based on Protein Pathway Array technology in gastric cancer
Lian, GD;Li, LP;Ye, F;Wang, DG;Liu, JL;Shi, YL;Jing, CQ;Suo, J;Zhang, DY;Chen, M
ONCOLOGY REPORTS 2018年 39卷1期 页码:307-315
RANDOMIZED CONTROLLED-TRIAL; ADJUVANT CHEMOTHERAPY; THERAPEUTIC TARGETS; LUNG-CANCER; 5-FLUOROURACIL; RESISTANCE; SURGERY; CELLS; MODEL; PREDICTION
The present study was aimed to identify proteins associated with signaling pathways involved in chemoresistance, and establish a predictive model for chemoresistance in gastric cancer patients after radical surgery. A total of 140 clinically-staged III gastric cancer samples from patients after D2 radical gastrectomy were enrolled in the present study. Protein Pathway Array (PPA) and 286 antibodies were used to assess the protein expression in tumor tissues of patients. The Significance Analysis of Microarray (SAM) software and clustering and discriminant analysis were used to identify differentially expressed proteins between chemosensitive and chemoresistant subsets, and a predictive model for chemoresistance was established using the independent predictive factors. The Ingenuity Pathway Analysis (IPA) software was also used to investigate the relationship between proteins and the signaling transduction network. A total of 23 proteins were differentially expressed between 67 chemosensitive and 73 chemoresitant tumor tissues. Six proteins including PLK1 and DACH1 were independent risk factors for chemoresistance. A predictive model for chemoresistance by these proteins was established, and the accuracy, the sensitivity, and the specificity of this modal was 89.3, 90.3 and 88.2%, respectively. In addition, the present study revealed that differentially expressed proteins were closely related to cellular activity, DNA methylation and DNA damage and repair, and also involved in the ERK/MAPK, Wnt/beta-catenin, PI3K/AKT, apoptosis and p53 signaling pathways. In conclusion, the predictive model established by PPA may be an effective detection system for predicting the chemosensitivity of gastric cancer patients after D2 gastrectomy.
Circulating miR-1826 in plasma correlates with circulating tumor cells and is a prognostic marker in colorectal cancer
Xu, ZH;Xi, TY;Han, Y;Guo, XB;Liu, F;Jiang, M;Wan, DW;Xue, XF;He, SB;Ren, R;Li, W;Zhi, QM
TUMOR BIOLOGY 2017年 39卷5期
CLINICAL-SIGNIFICANCE; BIOMARKERS; MICRORNAS; EXPRESSION; COMPLEMENTARY; RESISTANCE; CARCINOMA; SURVIVAL; CONFERS; GROWTH
Our previous study showed that miR-1826 was a newly identified oncogenic non-coding RNA in colorectal cancer. But the potential relationship between miR-1826 and tumor metastasis has not been fully elucidated. The purpose of this study was to evaluate the clinical significance of circulating miR-1826 and its possible associations with circulating tumor cells in colorectal cancer. Our results first found that serum miR-1826 was significantly upregulated in colorectal cancer patients, compared with that in healthy volunteers (p = 0.003). Similar results were also found in colorectal cancer with distant metastasis (p = 0.001) and advanced colorectal cancer (p < 0.001) patients, respectively. Clinicopathological analysis implied that circulating miR-1826 was positively associated with pT stage (p = 0.026), lymphatic metastasis (p = 0.034), distant metastasis (p = 0.012), and tumor-node-metastasis stage (p = 0.020). Besides, our univariate and multivariate analyses demonstrated that high serum miR-1826 expression could act as a prognostic and independent factor for overall survival of colorectal cancer patients (p < 0.05), which led to a poorer 5-year overall survival rate (p = 0.025). The area under the curve value of circulating miR-1826 was up to 0.848 +/- 0.043, which strongly suggested serum miR-1826 as an effective diagnostic biomarker in colorectal cancer patients (p < 0.001). Our subsequent experiments demonstrated that patients with high level of circulating tumor cells showed a higher level of miR-1826 expression, compared with the circulating tumor cell-negative patients (p = 0.011). Similar results also showed that the amount of circulating tumor cells in high miR-1826 group was significantly higher than that in low miR-1826 group (p = 0.001). Furthermore, the relationship between serum miR-1826 and circulating tumor cells was analyzed using SPSS software and a significant logarithmic relationship was found, which meant that circulating miR-1826 closely correlated with the amount of circulating tumor cells in colorectal cancer patient serum (r = 0.283, p < 0.01). Our findings strongly suggested that serum miR-1826 could serve as an effective and non-invasive biomarker for diagnosis and prognosis of colorectal cancer. Circulating miR-1826 may be an important target in colorectal cancer therapy.
Tetrandrine reverses the drug resistance of colon cancer to 5-fluorouracil
Wang, KL;Ma, LN;Bu, GB;Ma, G;Zhang, GD;Li, LP;Jing, CQ;Qin, CK
BIOMEDICAL RESEARCH-INDIA 2017年 28卷11期 页码:4843-4848
MEDIATED MULTIDRUG-RESISTANCE; CARCINOMA-CELLS; P-GP; INHIBITION; LEUKEMIA
Aim: Treatment for colon cancer is based mainly on the different stage of the cancer and chemotherapy is used as additional therapeutic approaches. 5-Fluorouracil (5-Fu) treatment is a conventional chemotherapeutical drug for colorectal cancer. However, a large amount of patients cannot be benefit from this therapy due to the resistance against 5-Fluorouracil displayed by their tumor. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid, exerts antitumor effects on certain kinds of cancers. Here, we elucidate the potential application of tetrandrine to eradicate the resistance of colon cancer against 5-Fluorouracil.;-;Methods: Colon cancer LOVO cell line and its 5-Fu-resistanct variant, LOVO/5-Fu, were employed in this study. Those two types of cells were treated with TET for 48 hours. Afterwards, cell viability was measured by MTT colorimetric assay. Cell cycle and apoptosis were determined by flow cytometry assay. P-glycoprotein (P-gp) is believed playing a major role in the anti-drug effect of tumor cells. Thus the expression of P-gd both in mRNA and protein level were analyzed with quantitative PCR and Western blot respectively.;-;Results: After LOVO/5-Fu cells were treated with TET for 48h, the IC50 of 5-Fu was significantly decreased to 4.15 +/- 0.31 mu g/ml (P<0.05); and the apoptotic rate were increased to 3.82% +/- 0.12% (P<0.05). Coincidently, the expression of P-gp mRNA was significantly decreased to 570 +/- 85 (P<0.05) and protein level of P-gp was also reduced respectively.;-;Conclusions: TET increased the sensitivity and reversed the drug-resistance of colon carcinoma cells to 5-Fu, which is relied on a P-gp-dependent manner.
Compound K, a metabolite of ginseng saponin, induces apoptosis of hepatocellular carcinoma cells through the mitochondria-mediated caspase-dependent pathway
Dong, X;Han, HB;Shi, HZ;Wang, TR;Wang, BY;Zhao, J
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE 2017年 10卷7期 页码:11146-11156
ATTENUATES METASTATIC GROWTH; LUNG-CANCER CELLS; CYCLE PROGRESSION; IN-VITRO; RESISTANCE; ARREST; MODEL
Compound K (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to possess the potential ability in preventing tumor development and suppressing cancer growth. However, the exact mechanism of its antitumorigenic effects is still not clear. The purpose of this project was to detect whether CK has an anticancer effect on hepatocellular carcinoma (HCC) cells, and to further explore the possible mechanisms. The Hep-G2 cells and xenograft in nude mice were used as models to study the anticancer effect of CK. Methylthiazolyldiphenyl-tetrazolium-bromide (MTT) assay showed that CK significantly inhibited the viabilities of Hep-G2 cells in dose-and time-dependent manners. In addition, flow cytometry analysis showed that CK induced apoptosis and cell cycle arrest in Hep-G2 cells, which possibly accounted for the antiproliferative effects of CK. Notably, the data in the present research indicated that CK upregulated the expression of p21(Cip1) and p27(Kip1), and downregulated the expression of cyclin D1 and cyclin-dependent kinase 4, causing a G0/G1 phase arrest, blocking cell cycle progression, and inducing apoptosis in the Hep-G2 cells, which was mediated by the mitochondrial pathway through a modulation of the ratio of Bcl-2 to Bax. In vivo studies showed that tumor volume, compared with control group, was reduced dramatically in CK-treated group. Therefore, the present study provides new insights that CK may be an potential agents in the prevention or treatment of HCC.
RhoA/ROCK1 signaling pathway is involved in proliferation and differentiation in human lung fibroblast cells
Ma, DD;Xie, DT;Chu, YF;Li, CP;Chen, M;Zhang, LL;Zhang, JC;Wang, CT
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017年 10卷5期 页码:6170-6178
MICROVASCULAR ENDOTHELIAL-CELLS; RESPIRATORY-DISTRESS-SYNDROME; PULMONARY-FIBROSIS; BARRIER DYSFUNCTION; COLLAGEN SECRETION; INHIBITION; MYOFIBROBLASTS; FASUDIL; INJURY; PHOSPHORYLATION
Pulmonary fibrosis, a secondary effect of other diseases such as sepsis-associated ARDS, interferes with a patient's ability to breathe. The control of proliferation and differentiation become a strategy for treating pulmonary fibrosis. In this study, we want to explore the effects of Lipopolysaccharide (LPS) on the activity of RhoA/ROCK1 signaling pathways, and tried to explore the mechanism of the signaling pathways in MRC-5 cells proliferation and differentiation. We divided cells into four groups, control group, LPS group, LPS + low-dose Fasudil (15 mu mol/ml) group and LPS + high-dose Fasudil (30 mu mol/ml) group. RhoA activity was determined by Rho pull-down analysis and the protein levels of GTP-RhoA, ROCK1, MYPT-1 (Myosin phosphatase target subunit), p-MYPT-1 (a downstream substrate of ROCK1) and alpha-smooth muscle (alpha-SMA, a marker of myofibroblast cells differentiation) were determined by Western blot. Real-time PCR was used to determine the level of alpha-SMA mRNA. Cell proliferation rate was examined using CCK-8 and EdU Imaging Kit. LPS up-regulated RhoA activity, protein expressions of ROCK1, p-MYPT-1 and alpha-SMA as well as proliferation rate (P<0.05). Furthermore, the effects mentioned above were inhibited by Fasudil (a highly selective inhibitor of ROCK) in dose-dependent manner. The significant higher inhibitory effects in high-dose Fasudil group were observed compared with low-dose Fasudil. Our data suggest that LPS induced MRC-5 cells proliferation and differentiation via RhoA/ROCK1 signaling pathways. Fasudil attenuated LPS-induced cells proliferation and differentiation by inhibiting this signaling pathway. Regulating RhoA/ROCK1 signaling pathway could be a potential new target to treat pulmonary fibrosis.
The Diagnostic Efficacy and Biological Effects of microRNA-29b for Colon Cancer
Li, LP;Guo, Y;Chen, YZ;Wang, JS;Zhen, L;Guo, XB;Liu, JL;Jing, CQ
TECHNOLOGY IN CANCER RESEARCH & TREATMENT 2016年 15卷6期 页码:772-779
COLORECTAL-CANCER; CORD BLOOD; CELLS; DIFFERENTIATION; EXPRESSION; DISEASE; MARKERS; RISK
Background: Colorectal cancer is one of the most common cancers worldwide in terms of both incidence and mortality. The associations of expressions of tissue and plasma miR-29b were not detected in this study. Methods: There are 400 healthy age-and gender-matched controls enrolled in this study in a rate of 1:2. The receiver operating characteristic curve analysis was undertaken using the expression level for miR-29b in the colorectal cancer specimens from patients with cancer and healthy controls to assess the diagnostic accuracy of both tissue and plasma miR-29b levels. Results: It was found that the expression of plasma miR-29b is associated with the tissue miR-29b. Advanced study showed that aberrant miR-29b expression in both cancer tissues and plasma is associated with the clinicopathological data of patients with colorectal cancer. Tissue miR-29b showed an AUC of 0.883, with a sensitivity of 81.6% and a specificity of 84.9%. However, the AUC for plasma miR-29b was 0.743, with a sensitivity of 61.4% and a specificity of 72.5%. The analyses of the biological effects of miR-29b for colorectal cancer showed that miR-29b could inhibit the cell viability and migration. Conclusion: In summary, our data suggest that both the tissue and the plasma miR-29b levels have some value as a diagnostic tool for colorectal cancer. Advanced biological effects were conducted to detect the potential effect on the cell viability and migration. Future investigations including larger patient populations and patients with early-stage colorectal cancer are needed to confirm the potential diagnostic value of miRNA-29b in colorectal cancer.
NLRP2 is highly expressed in a mouse model of ischemic stroke
Sun, X;Song, X;Zhang, L;Sun, J;Wei, XB;Meng, LY;An, J
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2016年 479卷4期 页码:656-662
INFLAMMASOME; ASSOCIATION; MICROGLIA; DISEASES; SYSTEM; INJURY; BETA
Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors with a major role in innate immunity. Fourteen of the twenty-two human NLRs contain a pyrin domain and form the NLRP subfamily (NLRPs). Among NLRPs, NLRP2 is less well understood in aspects of distribution and functions, especially in central nervous system (CNS). This study was the first to explore the expression of NLRP2 in central nervous system both under normal conditions and in ischemic stroke models. We found NLRP2 protein had a basal level of expression in CNS, mainly in astrocytes and was significantly elevated in ischemic brains in vivo or oxygen-glucose deprivation-treated cells in vitro. And silencing of NLRP2 genes could reduce the apoptotic rate of oxygen-glucose deprivation-treated cells. Thus high expression of NLRP2, especially in astrocytes, may play important roles in the pathophysiological process of ischemic stroke and has potential clinical value for the treatment of ischemic stroke. (C) 2016 Elsevier Inc. All rights reserved.
Long noncoding RNA OR3A4 promotes metastasis and tumorigenicity in gastric cancer
Guo, XB;Yang, ZG;Zhi, QM;Wang, D;Guo, L;Li, GM;Miao, RZ;Shi, YL;Kuang, YT
ONCOTARGET 2016年 7卷21期 页码:30276-30294 影响因子:5.008
TAX-MEDIATED TUMORIGENESIS; VEGF-C EXPRESSION; IN-VIVO; VASCULOGENIC MIMICRY; PROSTATE-CANCER; GENE-EXPRESSION; DOWN-REGULATION; CELL-MIGRATION; BREAST-CANCER; CARCINOMA
The contribution of long noncoding RNAs (lncRNAs) to metastasis of gastric cancer remains largely unknown. We used microarray analysis to identify lncRNAs differentially expressed between normal gastric tissues and gastric cancer tissues and validated these differences in quantitative real-time (qRT)-PCR experiments. The expression levels of lncRNA olfactory receptor, family 3, subfamily A, member 4 (OR3A4) were significantly associated with lymphatic metastasis, the depth of cancer invasion, and distal metastasis in 130 paired gastric cancer tissues. The effects of OR3A4 were assessed by overexpressing and silencing OR3A4 in gastric cancer cells. OR3A4 promoted cancer cell growth, angiogenesis, metastasis, and tumorigenesis in vitro and in vivo. Global microarray analysis combined with RT-PCR, RNA immunoprecipitation, and RNA pull-down analyses after OR3A4 transfection demonstrated that OR3A4 influenced biologic functions in gastric cancer cells via regulating the activation of PDLIM2, MACC1, NTN4, and GNB2L1. Our results reveal OR3A4 as an oncogenic lncRNA that promotes tumor progression, Therefore, lncRNAs might function as key regulatory hubs in gastric cancer progression.
Differentiation of pancreatobiliary-type from intestinal-type periampullary carcinomas using 3.0T MRI
Bi, L;Dong, Y;Jing, CQ;Wu, QZ;Xiu, JJ;Cai, SF;Huang, ZQ;Zhang, J;Han, X;Liu, QW;Lv, SC
JOURNAL OF MAGNETIC RESONANCE IMAGING 2016年 43卷4期 页码:877-886
APPARENT DIFFUSION-COEFFICIENT; AMPULLARY CARCINOMA; SMALL-BOWEL; ADENOCARCINOMA; VATER; DIAGNOSIS; SURVIVAL; GRADE; TUMOR; CHOLANGIOPANCREATOGRAPHY
PurposeTo differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas using combined magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced MRI, and diffusion-weighted imaging (DWI).;-;Materials and MethodsMRI (3.0T) results of 41 patients with pathologically confirmed periampullary carcinoma were retrospectively assessed. Two radiologists, blinded to histologic type of each tumor, evaluated image findings independently. MRCP image features, enhancement pattern, and apparent diffusion coefficient (ADC) values were analyzed. Independent-sample t-test, chi-square, or Fisher's exact test were used to determine differential image findings between the pancreatobiliary-type and the intestinal-type group. Cohen's statistic or interclass correlation coefficient (ICC) were used to evaluate interobserver agreement between two observers. Univariate and multiple logistic regression analysis were performed to identify MRI features with predictive values.;-;ResultsOn the basis of hematoxylin-eosin staining, 27 patients were classified as having pancreatobiliary-type carcinomas, and 14 patients the intestinal type. The pancreatobiliary-type carcinomas more commonly showed progressive enhancement than the intestinal type (P=0.003). The minimum ADC (ADC(min)) value of the pancreatobiliary-type group ([0.950.21] x 10(-3) mm(2)/s) was significantly lower than the intestinal-type group ([1.10 +/- 0.25] x 10(-3) mm(2)/s) (P=0.047). For interobserver agreement, the values and ICCs for all parameters exceeded 0.8, indicating almost perfect agreement. At multiple logistic regression analysis, the enhancement pattern was the only significant independent predictor (P=0.011, odds ratio [OR]=0.105). When the enhancement pattern and ADC(min) were used in combination, we could identify 70.4% of pancreatobiliary-type and 78.6% of intestinal-type carcinomas.;-;ConclusionProgressive enhancement and low ADC(min) values suggest a pancreatobiliary-type periampullary carcinoma. J. Magn. Reson. Imaging 2016;43:877-886
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