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Gao Y.,Chinese PLA General Hospital | Lu X.-C.,Chinese PLA General Hospital | Yang H.-Y.,Fourth Peoples Hospital of Jinan | Liu X.-F.,Chinese PLA General Hospital | And 2 more authors.
International Journal of Molecular Medicine | Year: 2012

The aim of this study was to identify the molecular mechanisms and biological pathways associated with the anticancer effects of atorvastatin. For this purpose, we conducted cell-based microarray and bioinformatic analyses to determine the effect of atorvastatin exposure on endothelial cell response. The results of bioinformatic analysis performed using the Connectivity Map (cMap) to examine the atorvastatin-induced changes in gene expression in the human umbilical vein endothelial cell line, EA.hy926, indicated that treatment with 10 μM of atorvastatin for 24 h upregulated the expression of 295 genes and downregulated the expression of 354 genes by 2-fold compared to the control treatment. The gene set enrichment analysis (GSEA), the Database for Annotation, Visualization and Integrated Discovery (DAVID) pathway analysis, and Gene Ontology (GO) analysis of differentially expressed genes revealed that Kruppel-like factors (KLFs) and cell cycle-related genes were the genes most significantly affected by atorvastatin treatment. The upregulation of KLFs and the downregulation of the cell cycle-related genes, including cyclin (CCN)A2, CCNE2, CCNB1 and CCNB2, were validated by real-time polymerase chain reaction (RT-PCR). A comparison of the gene expression profile of atorvastatin-treated cells with that of the control cells and with that of 6,100 compounds in the cMap database revealed that the profile of atorvastatin-treated cells was highly similar to that of histone deacetylase (HDAC) inhibitor-treated cells. Therefore, these results suggest that atorvastatin acts as an HDAC, a G1/S (start) and a G2/M (mitosis) cell cycle inhibitor. These findings provide evidence of the feasibility of the use of atorvastatin as an anticancer drug. Source

Zhang S.,Shandong University | Yu H.,Cancer Research Institute of Shandong Province | Zhang L.,Fourth Peoples Hospital of Jinan
Oncology Letters | Year: 2010

The present study was designed to investigate the role of vascular endothelial growth factor receptor (VEGFR)-3/Flt-4 in the early stages of cervical cancer. VEGFR-3/Flt-4 expression, vascular endothelial growth factor (VEGF)-C and VEGF-D in the early stages (Ia-IIa) of cervical cancer in 41 patients was examined by immunohistochemical analysis. Additionally, the VEGFR-3/Flt-4-marked vascular density (MVD) was examined and the relationship of these factors with clinicopathological factors was analyzed. VEGFR-3/Flt-4 was found to be expressed in lymphatic endothelial cells and, to a certain extent, in vascular endothelial cells. The VEGFR-3/Flt-4-positive vessels were largely distributed in the stroma surrounding the tumor tissues, and these vessels were morphologically divided into blood and lymphatic vessels, respectively. Cancer cells were found to express VEGF-C, VEGF-D and VEGFR-3/Flt-4, and their positive expression rate was 48.7% (20/41), 58.5% (24/41) and 63.4% (26/41), respectively. VEGFR-3/Flt-4 expression in the cancer cells of the cervical cancer patients in our study was found to be correlated to the clinical stage, lymph node metastasis, lymphatic invasion and expression of VEGF-C and VEGF-D. However, this expression was unrelated to menstrual status, histological grade and histological classification. MVD was correlated to the clinical stage and expression of VEGF-C and VEGF-D, but was unrelated to menstrual status, histological grade, histological classification, lymph node metastasis and lymphatic invasion. In conclusion, VEGFR-3/Flt-4 plays an important role in the early stages of cervical cancer. Source

Lu S.,Shandong University | Cui Y.,Fourth Peoples Hospital of Jinan | Li X.,Shandong University | Zhang H.,Shandong University | And 4 more authors.
Fertility and Sterility | Year: 2014

Objective To evaluate intracytoplasmic sperm injection (ICSI) results with regard to congenital bilateral absence of vas deferens (CBAVD) versus non-CBAVD obstruction, cystic fibrosis transmembrane-conductance regulator (CFTR) mutations versus non-CFTR mutations, and miscarriages or stillbirths versus live births per embryo transferred. Design Retrospective study with detailed chart review. Setting Center for reproductive medicine. Patient(s) Nine hundred forty-five men with obstructive azoospermia. Intervention(s) One thousand four hundred fourteen ICSI cycles classified as CBAVD versus non-CBAVD obstruction, CFTR mutations versus non-CFTR mutations, and miscarriages/stillbirths versus live births per embryo transferred. Main Outcome Measure(s) Frequency of CFTR mutations and rates of fertilization, good embryos, clinical pregnancy, miscarriages and stillbirths, ectopic pregnancy, and live births. Result(s) CFTR mutations were more prevalent in men with CBAVD than in those with non-CBAVD obstruction. The rate of miscarriages and stillbirths per embryo transferred was higher in men with CBAVD than in those with non-CBAVD obstruction, whereas the rate of live births per embryo transferred was lower in men with CBAVD than in those with non-CBAVD obstruction. The rate of miscarriages and stillbirths per embryo transferred was higher in men with CFTR mutations than in those with non-CFTR mutations. The frequency of CFTR mutations was higher in patients who experienced miscarriages/stillbirths than in those with live births. Conclusion(s) The frequency of CFTR mutations was higher in cases of CBAVD versus non-CBAVD obstruction. Possibly as a result of CFTR mutations, patients with CBAVD had a significantly increased risk of miscarriage and stillbirth and a reduced rate of live birth compared with patients with non-CBAVD. Copyright © 2014 American Society for Reproductive Medicine, Published by Elsevier Inc. Source

Yang M.,Shandong University | Wang J.,Fourth Peoples Hospital of Jinan | Wang L.,Shandong University | Wang L.,Shandong Academy of Sciences | And 7 more authors.
Prostate | Year: 2015

BACKGROUND The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. METHODS Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor β (ERβ), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERβ and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERβ and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. RESULTS SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17β-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERβ and AR. Knockdown of AR or ERβ blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERβ and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERβ expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. CONCLUSION These findings suggest that SOX4 is a novel DHT-repressed AR-target gene. E2 could promote proliferation of PCa cells through the up-regulation of SOX4 under androgen-depleted environment. Our data provides a possible molecular basis for the overexpression of SOX4 in CRPC and may facilitate the detection and prevention of the emergence of CRPC. © 2015 Wiley Periodicals, Inc. Source

Zhang H.,Air Force General Hospital of PLA | Gao H.,Fourth Peoples Hospital of Jinan | Liu C.,Air Force General Hospital of PLA | Kong Y.,Air Force General Hospital of PLA | Wang C.,Air Force General Hospital of PLA
Diagnostic Pathology | Year: 2015

Background: It has been shown that heat shock-related 70-kDa protein 2 (HSPA2), a member of the HSP70 family of heat shock proteins, is important for cancer cell growth and metastasis. However, the status of HSPA2 expression and its prognostic significance in pancreatic cancer remain unknown. Methods: Quantitative reverse transcriptase ploymerase chain reaction (qRT-PCR) was applied to examine HSPA2 messenger RNA (mRNA) expression in 104 pairs of pancreatic cancer tissues and adjacent noncancerous tissues. Statistical analyses were applied to evaluate the diagnostic value and associations of HSPA2 expression with clinicopathological characteristics. Results: HSPA2 mRNA was significantly overexpressed in pancreatic cancer tissues (3.9 ± 0.8) than in adjacent normal tissues (1.1 ± 0.4) (P < 0.001). Clinicopathological analysis showed that HSPA2 expression was significantly correlated with tumor size (P = 0.024), histological differentiation (P = 0.012), TNM stage (P = 0.006), lymph node metastasis (P = 0.043) and serum CA19-9 level (P = 0.046). Moreover, patients with higher HSPA2 expression levels had shorter overall survival time than those with lower HSPA2 expression levels (P = 0.019). Furthermore, Cox regression analyses showed that HSPA2 expression was an independent predictor of overall survival (P = 0.011). Conclusions: Our results suggest that overexpression of HSPA2 in pancreatic cancer is associated with aggressive progression and poor prognosis and that HSPA2 may be served as a prognostic marker. Source

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