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LBH589 Inhibits Glioblastoma Growth and Angiogenesis Through Suppression of HIF-1 alpha Expression
Yao, ZG;Li, WH;Hua, F;Cheng, HX;Zhao, MQ;Sun, XC;Qin, YJ;Li, JM
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 2017年 76卷12期 页码:1000-1007
HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; HISTONE DEACETYLASE INHIBITOR; PHASE-II; PANOBINOSTAT; ACETYLATION; TEMOZOLOMIDE; PROGRESSION; MECHANISMS; MULTIFORME; SURVIVAL
Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1 alpha instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis.
Angtensin II elicits a cAMP-dependent intestinal anion secretion by stimulating PGE2 release through ATI subtype receptors in rat ileum
Xiao, L;Liu, HW;Di, H;Chen, LX;Zhou, Q;Yu, X;Jing, HY;Tang, SH
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2017年 494卷1-2期 页码:207-212
RENIN-ANGIOTENSIN SYSTEM; CANINE TRACHEAL EPITHELIUM; IMMUNOHISTOCHEMICAL LOCALIZATION; GASTROINTESTINAL-TRACT; WATER-ABSORPTION; CL-CONDUCTANCES; CELLS; TRANSPORT; MEMBRANE; PEPTIDES
A growing literature has demonstrated that the renin-angiotensin system (RAS) involves in gut function. Angiotensin II (AnglI) stimulates Cl- secretion in intestine epithelial cells. However, the underlying signal pathway remains unexplored. Here, we explored that serosal application of Ang II (5 x 10(-8) M) significantly increased the baseline Isc compared to the control group in rat ileum. Tetrodotoxin (1TX) failed to suppress Isc evoked by Ang II. However, the Ang II-evoked Isc was significantly suppressed by the ATRi antagonist losartan instead of ATR2 antagonist PD123319. Of interest, both cyclooxygenase (COX)-1 inhibitor SC560 and COX-2 specific inhibitor ns398 blocked the Ang II-evoked Isc. Preincubation of submucosa/mucosa preparations with Ang II for 10 min significantly increased PGE2 production, which was abolished by either COX-1 or COX-2 inhibitor. In addition, the Ang II-induced PGE2 release was also attenuated by ATRi receptor antagonist rather than selective ATR2 receptor antagonist. Furthermore, preincubation of tissues for 15 min with forskolin, a cAMP activator, markedly blocked the Isc evoked by AnglI, while intracellular Ca2+ pump inhibitor thapsigargin, L-type Ca2+ channel blocker nicadipine or the epithelial Na+ channel blocker amiloride didn't show such function. These results suggest that Ang II evokes cAMP-activated intestinal anion secretion by stimulating PGE2 release through activation of ATR1. (C) 2017 Elsevier Inc. All rights reserved.
Peroxynitrite induces apoptosis of mouse cochlear hair cells via a Caspase-independent pathway in vitro
Cao, ZX;Yang, QQ;Yin, HY;Qi, Q;Li, HR;Sun, GY;Wang, HL;Liu, WW;Li, JF
APOPTOSIS 2017年 22卷11期 页码:1419-1430 影响因子:3.592
CISPLATIN-INDUCED OTOTOXICITY; ORGANOTYPIC CULTURES; HEARING-LOSS; RAT; GENES; DEATH; MICE; AIF; AGE
Peroxynitrite (ONOO-) is a potent and versatile oxidant implicated in a number of pathophysiological processes. The present study was designed to investigate the effect of ONOO- on the cultured cochlear hair cells (HCs) of C57BL/6 mice in vitro as well as the possible mechanism underlying the action of such an oxidative stress. The in vitro primary cultured cochlear HCs were subjected to different concentrations of ONOO-, then, the cell survival and morphological changes were examined by immunofluorescence and transmission electron microscopy (TEM), the apoptosis was determined by Terminal deoxynucleotidyl transferase dUNT nick end labeling (TUNEL) assay, the mRNA expressions of Caspase-3, Caspase-8, Caspase-9, Apaf1, Bcl-2, and Bax were analyzed by RT-PCR, and the protein expressions of Caspase-3 and AIF were assessed by immunofluorescence. This work demonstrated that direct exposure of primary cultured cochlear HCs to ONOO- could result in a base-to-apex gradient injury of HCs in a concentration-dependent manner. Furthermore, ONOO- led to much more losses of outer hair cells than inner hair cells mainly through the induction of apoptosis of HCs as evidenced by TEM and TUNEL assays. The mRNA expressions of Caspase-8, Caspase-9, Apaf1, and Bax were increased and, meanwhile, the mRNA expression of Bcl-2 was decreased in response to ONOO- treatment. Of interesting, the expression of Caspase-3 had no significant change, whereas, the expression alteration of AIF was observed. These results suggested that ONOO- can effectively damage the survival of cochlear HCs via triggering the apoptotic pathway. The findings from this work suggest that ONOO--induced apoptosis is mediated, at least in part, via a Caspase-independent pathway in cochlear HCs.
Spindle cell subtype of pulmonary clear cell tumor with prominent calcification and malignant potential
Song, YH;Chen, FF;Zhang, CQ;Lin, XY
THORACIC CANCER 2017年 8卷5期 页码:530-534
CD1A EXPRESSION; PECOMAS; LUNG
Perivascular epithelioid cell tumor of the lung, also known as clear cell sugar tumor, is a rare benign tumor arising from perivascular epithelioid cells. Herein, we present a case of spindle cell subtype of pulmonary perivascular epithelioid cell tumor with prominent calcification and malignant potential in a 49-year-old woman. Histologically, the striking feature of this lesion was attributed to the presence of spindle cells arranged in a diffuse pattern, which is a pitfall for diagnosis. However, some of the lesion contained polygonal tumor cells with clear abundant cytoplasm surrounded by thin-walled vascular spaces. The size of the tumor and its Ki-67 index suggested malignant potential, and calcification was another rare characteristic. Immunostaining indicated that the tumor cells were positive not only for HMB-45 and Melan A, but also for CD34 and CD1a. This tumor should be distinguished from tumors with rich spindle cells such as sarcoma, clear cell carcinoma, or metastatic tumors. The patient in this case was alive with no tumor recurrence or metastasis sixmonths after lobectomy.
Downregulation of esophageal cancer-related gene 4 promotes proliferation and migration of hepatocellular carcinoma
Ge, SJ;Xu, YL;Wang, HL;Sun, YX;Tian, XG;Cao, ZX;Lin, XY;Xu, JW;Wang, QX
ONCOLOGY LETTERS 2017年 14卷3期 页码:3689-3696
EPITHELIAL-MESENCHYMAL TRANSITION; ECRG4; CELLS; EXPRESSION; OVEREXPRESSION; METASTASIS; APOPTOSIS; INVASION; GLIOMA
Esophageal cancer-related gene 4 (ECRG4) is a candidate tumor suppressor gene, which is involved in cell apoptosis, migration, infection and inflammation responsiveness; however, its expression level and clinical significance in hepatocellular carcinoma (HCC) remains unclear. In the present study, the authors aim to evaluate the clinical significance and potential role of ECRG4 in HCC. Level of ECRG4 protein expression in HCC and peripheral tissues was investigated in tissue specimens obtained from 56 consecutive HCC patients by immunohistochemistry. Cell proliferation, cell migration and invasion regulations were examined by MTT curves, flow cytometry, Transwell assays and western blotting. ECRG4 expression was weak positive in normal liver cells but was downregulated in HCC cells in vivo or in vitro. A decreased expression of ECRG4 was associated with the age of the patients, metastasis and Ki-67 proliferation index. However, decreased ECRG4 expression was not associated with differentiation, tumor size, the presence of portal vein tumor thrombosis, satellite lesions, tumor relapse or mortality. Further investigations revealed that ectopic expression of ECRG4 inhibited cell proliferation, migration and invasion and promoted cell apoptosis in SMMC-7721 cells, which was mediated by the regulation of BAX and B cell lymphoma-2, in addition to the upregulation of epithelial-mesenchymal transition markers. In conclusion, the results of the present study indicated that ECRG4 was downregulated in HCC and served important roles in promoting cell proliferation and migration.
Pulmonary pleomorphic carcinoma A case report and review of the literature
Zhang, XW;Wang, Y;Zhao, LP;Jing, HY;Sang, SW;Du, JJ
MEDICINE 2017年 96卷29期
LUNG
Rationale: Pleomorphic carcinoma (PC) is a rare malignancy of the lung. It has a dual-cell component of spindle and/or giant cells, and of epithelial cells.;-;Patient Concerns and Diagnoses: We presented a case of PC. A 69-year-old healthy asymptomatic woman who was occasionally found an abnormal shadow on her chest X-rays. A computerized tomography scan showed a mass located in the left lingular lobe and the percutaneous lung biopsy pathology confirmed sarcomatoid cancer.;-;Interventions and Outcomes: The patient underwent pneumonectomy. A diagnosis of PC was confirmed after surgery through immunohistochemistry. The pathological stage was T2aN0M0 (Ib). Due to the patient's refusal, adjuvant chemotherapy was not taken and she has been living disease free for 12 months after the surgery.;-;Lessons: PC of the lung represents a rare pathological entity. Surgical resection remains the cornerstone of the treatment and may offer the possibility of long-time survival in early-stage patients. More cases of PC should be reported to establish an optimal management.
HCRP1 inhibits TGF-beta induced epithelial-mesenchymal transition in hepatocellular carcinoma
Yang, W;Wang, JG;Xu, JW;Zhou, DM;Ren, KH;Hou, CJ;Chen, LL;Liu, XP
INTERNATIONAL JOURNAL OF ONCOLOGY 2017年 50卷4期 页码:1233-1240
CANCER; EXPRESSION; PROGNOSIS; PROTEIN
Hepatocellular carcinoma-related protein 1 (HCRP1), also known as human vacuolar protein sorting 37 homologue A (hVps37A), has not been detected or is significantly downregulated in hepatocellular carcinoma (HCC) tissues. However, information on the regulatory mechanisms of HCRP1 in HCC remains unclear. Here we found that the downregulation of HCRP1 in HepG2 cells (with low invasion capacity) significantly enhanced migration and invasion, whereas HCRP1 upregulation in SMMC-7721 cells (with high invasion capacity) generated the opposite result. Interestingly, the morphology of HepG2 cells significantly changed from an epithelial to mesenchymal phenotype after HCRP1 knockdown. Moreover, we observed a decrease in the expression of epithelial cell markers E-cadherin and beta-catenin, and an increase in the expression of mesenchymal cell markers N-cadherin and vimentin. We also observed that the downregulation of HCRP1 induced epithelial-mesenchymal transition (EMT) through the transforming growth factor-beta pathway. Together, our findings define a novel function for HCRP1 from the perspective of EMT, which is closely associated with the migration and invasion of HCC cells.
HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition
Xu, JW;Zhang, X;Wang, HL;Ge, SJ;Gao, TH;Song, L;Wang, XX;Li, H;Qin, YJ;Zhang, ZH
BIOMEDICINE & PHARMACOTHERAPY 2017年 88卷 页码:421-429
CANCER-CELLS; EXPRESSION; METASTASIS; GROWTH; PROLIFERATION; PROGNOSIS; RNA; EMT
Hepatocellular carcinoma related protein 1 (HCRP1), which is essential for internalization and degradation of ubiquitinated membrane receptors, is downregulated in several tumors and strongly affects the outcomes of cancer patients. It is reported the expression of HCRP1 is inversely related to epidermal growth factor receptor (EGFR) in breast cancer and lead to resistance to cetuximab in ovarian cancer. However, its exact mechanism in the progression of Hepatocellular carcinoma (HCC) remains unknown. Herein, HCRP1 expression and its clinical significance were examined in 101 HCC patients using immunohistochemistry. Cell proliferation, migration and invasion assays were conducted in HCC cell lines. EGFR activation and degradation were then observed after EGF inducing in HCRP1 knockdown HepG2 cells. In addition, we also detected whether epithelial-to-mesenchymal transition (EMT) was involved in the malignancy promoted by HCRP1. The results showed that 59 of the 101 HCC cases exhibited downregulation of HCRP1 expression (P < 0.01) as compared to 30 benign liver lesions and 20 normal liver tissues, all of which showed a high level of HCRP1. HCRP1 expression was significantly related to age (P = 0.017), pathological grade (P = 0.003), tumor encapsulation (P = 0.037), recurrence (P = 0.039) and death (P = 0.015), but unrelated to cirrhosis (P = 0.216), tumor size (P = 0.273), and distant metastasis (P = 0.554). Lower HCRP1 expression was correlated with shorter RFS and OS (P < 0.001), and decreased HCRP1 level is an independent prognostic marker in HCC patients (P < 0.05). Overexpression of HCRP1 decreased and knockdown increased HCC cell proliferation, migration and invasion. HCRP1 depletion increased EGFR activation and inhibited EGFR degradation. EMT phenotype was promoted after HCRP1 downregulation via increase of Snail and Twist1 and activation of Akt phosphorylation in HepG2 cells. Conversely, upregulation of HCRP1 in SMMC-7721 cells led to the opposite effect. In conclusion, our study indicated that downregulation of HCRP1 is a valuable prognostic factor involved in EGFR regulation and acquisition of the mesenchymal phenotype of HCC cells. (C) 2017 Elsevier Masson SAS. All rights reserved.
Correlation of cancer stem cell markers and immune cell markers in resected non-small cell lung cancer
Huang, ZQ;Yu, HN;Zhang, JB;Jing, HY;Zhu, WQ;Li, XL;Kong, LL;Xing, LG;Yu, JM;Meng, XJ
JOURNAL OF CANCER 2017年 8卷16期 页码:3190-3197
INITIATING CELLS; CD133 EXPRESSION; STAGE; INFILTRATION; DOCETAXEL; NIVOLUMAB; BIOLOGY; IMPACT; TUMORS; OCT4
Background: Recent studies confirmed that immunotherapy showed prominent efficacy in non-small cell lung cancer (NSCLC). Cancer stem cells/cancer initiating cells are resistant to anticancer treatment. The purpose of the study was to analyze the correlation of cancer stem cells/cancer initiating cells and tumor-infiltrating immune cells in NSCLC.;-;Methods: CD133, octamer 4 (OCT-4), CD8, CD56, human leukocyte antigen (HLA) class I and programmed death ligand-1 (PD-L1) were assessed in 172 resected NSCLC samples. The staining was analyzed and scored by the pathologist who was blinded to the clinical pathological data of the patients.;-;Results: High CD8+ T cell infiltration was correlated significantly with squamous cell carcinoma histology (p=0.008). High PD-L1 expression (>= 10%) was associated with high tumor status (p=0.043). Pearson's correlation test showed that CD56+ cells were negatively correlated with CD133 expression (r=-0.361, p<0.001) and weakly correlated with negative OCT-4 expression (r=-0.180, p=0.018). There was a strong positive correlation between CD8 and HLA class I (r=0.573, p<0.001). In the survival analysis, high CD8+ T cell infiltration is an independent predictor of improved disease-free survival and overall survival. Patients with low CD133 expression and high CD56 expression had a longer overall survival than those with high CD133 expression and/ or low CD56 expression (p=0.013).;-;Conclusion: There is a negative correlation between CD56+ cells and cancer stem cell markers. This correlation may confirm the possibility that natural killer cells can target CD133+ cancer stem cells/cancer initiating cells in non-small cell lung cancer.
Characterization of a Relatively Malignant Form of Osteopetrosis Caused by a Novel Mutation in the PLEKHM1 Gene
Bo, T;Yan, F;Guo, J;Lin, XY;Zhang, HQ;Guan, QB;Wang, H;Fang, L;Gao, L;Zhao, JJ;Xu, C
JOURNAL OF BONE AND MINERAL RESEARCH 2016年 31卷11期 页码:1979-1987
RAB7; RUBICON; CLASSIFICATION; PATHOGENESIS; DEFICIENCY; NOSOLOGY; REVISION; SUBUNIT; DOMAINS; PATHWAY
Osteopetrosis (OMIM: 611497), literally "stone bone," is a group of inherited bone disorders characterized by increased skeletal mass due to defective osteoclast function. A patient who reported a history of frequent fractures, weakness and fatigue was admitted to our hospital in 2011. The patient presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in bone mineral density (BMD). Aside from his father's complaint of excessive tooth loss, his mother, two sisters, son, and daughter were healthy. Blood samples of the family members were drawn for genetic analyses. The entire coding region and adjacent splice sites of the pleckstrin homology domain-containing family M (with RUN domain) member 1 (PLEKHM1) gene were sequenced. One mutation, a heterozygous deletion mutation in exon 11 (c.3051_3052delCA), was identified in the patient but not in his relatives. The mutation leads to a translation product with a highly impaired Rubicon homology domain. Co-immunoprecipitation and immunofluorescence analyses using HEK293 cells showed that overexpression of a PLEKHM1 CA-deletion mutant resulted in a dramatic decrease in the interaction between PLEKHM1 and the small GTPase Rab7 compared to wild-type PLEKHM1. The normal processes of endocytosis and autophagy were disturbed in cells expressing the mutant (transfected HEK293 and U937 cells), as indicated by epidermal growth factor receptor (EGFR) degradation and an altered LC3-I/II ratio, respectively, which may lead to a defect in osteoclast function. A four-year follow-up study of the patient showed that the PLEKHM1-dependent osteopetrosis was relatively malignant, with significant symptoms of pancytopenia and hepatosplenomegaly. (C) 2016 American Society for Bone and Mineral Research.
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