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ABSTRACT: OBJECTIVES: Oral squamous cell carcinoma (OSCC) accounts for>90% oral cancer which is a leading cause of cancer death worldwide. Early diagnosis may well offer an opportunity to increase survival to this neoplasm. Micro(mi)RNA-interfered cancer progression is crucial, yet its migration machinery of OSCC is still unknown. To access whether the possible miRNA prognostic markers and underlying mechanisms, we developed a highly migratory TW2.6 MS-10 cells from TW2.6 cells to investigate the issue. MATERIALS AND METHODS: miRNA profiling was performed on TW2.6 and TW2.6 MS-10. Target miRNA was correlated to pathological status in OSCC patients by real-time RT-PCR. A downstream effector was identified using a bioinformatics analysis, and a 3'-untranslated region (UTR) reporter assay was used. RESULTS: An miRNA cluster, miR-17-92, including miR-17, miR-19b, miR-20a, and miR-92a, was found to be significantly down-regulated in TW2.6 MS-10 compared to TW2.6 cells. Overexpression of this cluster decreased the migratory ability of OSCC cell lines. We further demonstrated that miR-17 and miR-20a are the main miRNAs of miR-17-92 cluster which modulate OSCC migration. Clinically, miR-17/20a showed negative correlation with TNM stage and lymphatic metastasis. Through a bioinformatics screening analysis and 3'UTR reporter assay, we confirmed the integrin (ITG) β8 as a direct target of miR-17/20a, and knockdown of ITGβ8 reduced cell migratory capability of OSCC. CONCLUSIONS: miR-17/20a acts as a prognostic predictor of OSCC patients' outcome and a tumor migration suppressor miRNA.
Oral Oncology 04/2013; · 2.86 Impact Factor
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ABSTRACT: OBJECTIVE.: The aims of the study were to examine the role of SIRT1/FoxO3a in Cyr61 expression in rheumatoid arthritis synovial fibroblasts (RASFs) and the influence of simvastatin on this pathway. In a model of collagen-induced arthritis (CIA), the relation between disease progression and FoxO3a/Cyr61 signaling in synovial fibroblasts (SFs) was assessed. METHODS.: Cyr61 and SIRT1 expressions, localization of FoxO3a in the nucleus/cytoplasm and phosphorylation/acetylation of FoxO3a were examined by Western blotting. CCL20 secretion was assessed by enzyme-linked immunosorbent assay. Promoter activity of Cyr61 gene was evaluated by luciferase assay with or without forced expression of FoxO3a and SIRT1 by lentiviral transduction. FoxO3a/Cyr61 promoter interaction was examined by chromatin immunoprecipitation. In CIA rats, expressions of Cyr61 and phospho-FoxO3a in SFs were examined by immunohistochemistry. RESULTS.: In RASFs, simvastatin suppressed TNF-α-induced Cyr61 and CCL20 production. TNF-ααdecreased nuclear expression of FoxO3a and forced expression of FoxO3a reversed the Cyr61-inductive effect of TNF-α. Simvastatin inhibited nuclear export, phosphorylation and acetylation of FoxO3a and maintained its binding to Cyr61 promoter. SIRT1 decreased Cyr61 expression and deacetylated FoxO3a whereas simvastatin upregulated SIRT1 and SIRT1/FoxO3a binding in RASFs. In rats with CIA, simvastatin alleviated arthritis and suppressed Cyr61 expression and FoxO3a phosphorylation in SFs. CONCLUSION.: Cyr61 is important in RA pathogenesis and SIRT1/FoxO3a signaling is crucial to Cyr61 induction in RASFs. Simvastatin is beneficial to inflammatory arthritis by upregulating SIRT1/FoxO3a signaling in SFs. Continued study of the pathways linking sirtuins, FoxO proteins and inflammatory responses of RASFs may provide new insights into the pathophysiology of RA. © 2012 American College of Rheumatology.
Arthritis & Rheumatism 12/2012; · 7.87 Impact Factor
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ABSTRACT: Chromosomal instability (CIN) is widely considered a hallmark of cancer but its precise roles in cancer stem cells (CSCs) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis and poor prognosis. Here we report that BMI1 mediates its diverse effects through upregulatiion of the mitotic kinase Aurora A which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed microRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exert several effects, including centrosomal amplification and aneuploidy, anti-apoptosis and cell cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that co-amplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT and CIN through the BMI1-AURKA axis and suggest therapeutic utility from inhibiting Aurora A in head and neck cancers which overexpress BMI1.
Cancer Research 11/2012; · 7.86 Impact Factor
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ABSTRACT: Stromal cell-derived factor-1 (SDF-1) (CXCL12) has been observed to promote laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) invasion through cooperation with its receptor CXCR4. Here, we further explore the angiogenesis mechanism induced by SDF-1/CXCR4 interaction in LHSCCs. Immunohistochemistry (IHC) reveals the significant correlation between CXCR4 and angiogenesis in tumors. After blocking the function of CXCR4 by specific inhibitor AMD3100 and neutralized antibody 12G5 or inhibiting the expression by siRNA, we were able to disrupt the HUVECs tube formation, demonstrating that SDF-1/CXCR4 indeed regulated the angiogenesis mechanism. The angiogenesis profiling from angiogenesis array and reverse transcription polymerase chain reaction indicates that IL-8 can be significantly triggered by SDF-1/CXCR4 interaction in LHSCCs. We also demonstrate that IL-8 secretion mechanism is regulated by Akt phosphorylation after SDF-1 stimulation. These results point out the importance of SDF-1/CXCR4 interaction in LHSCCs angiogenesis. The angiogenic factor IL-8 would be triggered by the cooperation of SDF-1 and CXCR4 through an Akt-dependent pathway. This provides a new targeting therapy utility, disrupting SDF-1/CXCR4 interaction combined with downstream-induced angiogenic factors in LHSCCs would be beneficial to improve clinical outcome.
Oral Oncology 02/2012; 48(6):507-15. · 2.86 Impact Factor
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ABSTRACT: Vascular endothelial growth factor-A (VEGF-A) affects tumor growth and metastasis through stimulation of angiogenesis. The purpose of this study was to describe features of Lewis lung cancer (LLC) in mice and compare the serum VEGF-A levels with those of normal control mice. Two groups of mice were compared: one was subcutaneously injected with LLC cells (n=16) and the other served as the normal control (n=6). The serum VEGF-A levels were measured by ELISA prior to inoculation, and at 7, 21 and 35 days post-inoculation. The tumor weight and the metastatic condition were evaluated on day 35. Changes in body weight and serum VEGF-A concentration over a period of time were compared between the groups using generalized estimating equations. The relationship between the primary tumor and the metastatic condition was analyzed using the Spearman's rank correlation test. The survival rate was 56.3% on day 35 post-tumor inoculation. No difference was found between the groups with regard to gastrocnemius muscle weight on day 35 post-inoculation [0.1315±0.0066 g vs. 0.1308±0.0069 g (normal control)]. In tumor-bearing mice, the weight gain at sacrifice was less (0.24±0.45 vs. 1.93±0.47 g, P=0.01), the final mean tumor volume and weight were 4264.69±1038.32 mm(3) and 3.70±0.83 g, the number of nodules in the lungs and livers was 6.33 (range 0-20) and 2.22 (range 0-11), respectively, and the serum VEGF-A levels were significantly higher than those of control mice. In conclusion, lower body weight gain, metastasis in the liver and lungs, and elevated VEGF-A levels are features of LLC in mice.
Oncology letters 11/2011; 2(6):1143-1147. · 0.11 Impact Factor
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Szu-Ta Chen,
Yung-Ming Jeng, Cheng-Chi Chang,
Hsiu-Hao Chang,
Min-Chuan Huang,
Hsueh-Fen Juan,
Chun-Hua Hsu,
Hsinyu Lee,
Yung-Feng Liao,
Ya-Ling Lee,
Wen-Ming Hsu,
Hong-Shiee Lai
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ABSTRACT: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported to enhance proliferation and invasion in various cancers. The role of IMP3 on neuroblastoma (NB) is unknown. We aimed to clarify the prognostic significance of IMP3 expression in patients with NB. By microarray analysis, high IMP3 expression was found in patients with poor outcome. IMP3 expression in 90 NB samples was analyzed by immunohistochemical staining to correlate with clinical stages, histology, and patient outcome. Positive IMP3 expression was detected in 52 of 90 patients, and was significantly correlated with undifferentiated histology, advanced stages, MYCN amplification, and poor outcome. In subgroups, positive IMP3 expression could predict an even worse prognosis in patients with advanced disease, with normal MYCN status, or with MYCN amplification (P = 0.005, P = 0.001, and P = 0.033, respectively). The IMP3 expression decreased by induction of differentiation with retinoid acid treatment in SK-N-DZ and SK-N-SH cells in vitro. The invasion ability of NB cells also decreased as IMP3 knockdown by using RNA interference in vitro. In summary, high expression of IMP3 in NB might contribute to the undifferentiated phenotype and invasive behaviors, leading to a poor prognosis. Determining IMP3 expression in NB could help to improve a personalized therapy.
Cancer Science 09/2011; 102(12):2191-8. · 3.33 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT) is important for organ development, metastasis, cancer stemness, and organ fibrosis. Molecular mechanisms to coordinately regulate hypoxia-induced EMT remain elusive. Here, we show that HIF-1α-induced histone deacetylase 3 (hdac3) is essential for hypoxia-induced EMT and metastatic phenotypes. Change of specific chromatin states is associated with hypoxia-induced EMT. Under hypoxia, HDAC3 interacts with hypoxia-induced WDR5, recruits the histone methyltransferase (HMT) complex to increase histone H3 lysine 4 (H3K4)-specific HMT activity, and activates mesenchymal gene expression. HDAC3 also serves as an essential corepressor to repress epithelial gene expression. Knockdown of WDR5 abolishes mesenchymal gene activation but not epithelial gene repression during hypoxia. These results indicate that hypoxia induces different chromatin modifiers to coordinately regulate EMT through distinct mechanisms.
Molecular cell 09/2011; 43(5):811-22. · 14.61 Impact Factor
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Szu-Hua Pan,
Yu-Chih Chao,
Pei-Fang Hung,
Hsuan-Yu Chen,
Shuenn-Chen Yang,
Yih-Leong Chang,
Chen-Tu Wu, Cheng-Chi Chang,
Wen-Lung Wang,
Wing-Kai Chan,
Yi-Ying Wu,
Ting-Fang Che,
Lu-Kai Wang,
Chien-Yu Lin,
Yung-Chie Lee,
Min-Liang Kuo,
Chau-Hwang Lee,
Jeremy J W Chen,
Tse-Ming Hong,
Pan-Chyr Yang
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ABSTRACT: Metastasis is a predominant cause of death in patients with cancer. It is a complex multistep process that needs to be better understood if we are to develop new approaches to managing tumor metastasis. Tumor cell invasion of the local stroma is suppressed by collapsin response mediator protein-1 (CRMP-1). Recently, we identified a long isoform of CRMP-1 (LCRMP-1), expression of which correlates with cancer cell invasiveness and poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). Here, we report that LCRMP-1 overexpression in noninvasive human cell lines enhanced filopodia formation, cancer cell migration, and invasion via stabilization of actin. This effect required a highly conserved N-terminal region of LCRMP-1 as well as the WASP family verprolin-homologous protein-1/actin nucleation pathway (WAVE-1/actin nucleation pathway). Furthermore, LCRMP-1 appeared to act downstream of Cdc42, a Rho family protein known to be involved in actin rearrangement. In addition, LCRMP-1 associated with CRMP-1, which downregulated cancer cell metastasis by interrupting the association of LCRMP-1 and WAVE-1. Finally, we found that high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with lymph node metastasis and poor survival in patients with NSCLC. In sum, we show that LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis and propose that this pathway may serve as a potential anticancer target.
The Journal of clinical investigation 08/2011; 121(8):3189-205. · 15.39 Impact Factor
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ABSTRACT: Bladder cancer is a common urothelial cancer. Through proteomic approaches, calreticulin (CRT) was identified and proposed as a urinary marker for bladder cancer. CRT is a multifunctional molecular chaperone that regulates various cellular functions such as Ca(2+) homeostasis and cell adhesion. CRT is overexpressed in various cancers, but its mechanism of action in the development of bladder tumors remains unclear. We generated J82 bladder cancer cells lines that either stably overexpressed or knocked down CRT to investigate the physiological effects of CRT on bladder tumors. Compared with the transfected control vector cells, the knockdown of CRT suppressed cell proliferation, migration, and attachment, whereas overexpression of CRT enhanced cell migration and attachment. We further demonstrated that the phosphorylation status of focal adhesion kinase and paxillin, important regulators of the focal adhesion complex, was also regulated in these cells. In contrast, phosphorylation of Src, a protein tyrosine kinase reported to be affected by CRT, was not significantly different between the control and CRT-RNAi groups. Most importantly, we observed that tumors derived from J82 CRT-RNAi cells were significantly smaller and had fewer metastatic sites in the lung and liver in vivo than did transfected control vector cells. In conclusion, our results suggest that alteration of CRT expression levels might affect bladder cancer progression in vitro and in vivo.
American Journal Of Pathology 06/2011; 179(3):1425-33. · 4.89 Impact Factor
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ABSTRACT: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression.
To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays.
CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK-mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples.
Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC.
Annals of Surgical Oncology 06/2011; 19 Suppl 3:S385-94. · 4.17 Impact Factor
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ABSTRACT: Here, we aimed to investigate the role of connective tissue growth factor (CTGF) in peritoneal carcinomatosis (PC) associated with colorectal cancer (CRC) and to characterize the underlying mechanism of CTGF mediating adhesion.
A cohort of 136 CRC patient specimens was analyzed in this study. CRC cell lines were used for in vitro adhesion assay and in vivo peritoneal dissemination experiment. Recombinant CTGF protein treatment, transfection of CTGF expression plasmids, and knockdown of CTGF expression in CRC cells were utilized to evaluate the integrin α5, which served as a target of CTGF in inhibiting peritoneal seeding.
The analysis of CRC tissues revealed an inverse correlation between CTGF expression and prevalence of PC. Lower CTGF level in CRC patients was associated with higher peritoneal recurrence rate after surgery. Inducing CTGF expression in cancer cells resulted in decreased incidence of PC and increased rate of mice survival. The mice received intraperitoneal injection of recombinant CTGF protein simultaneously with cancer cells or following tumor formation; in both cases, peritoneal tumor dissemination was found to be effectively inhibited in the mouse model. Functional assay revealed that CTGF significantly decreased the CRC cell adhesion ability, and integrin α5 was confirmed by reverse transcriptase PCR and functional blocking assay as a downstream effector in the CTGF-mediated inhibition of CRC cell adhesion.
CTGF acts as a molecular predictor of PC and could be a potential therapeutic target for the chemoprevention and treatment of PC in CRC patients.
Clinical Cancer Research 05/2011; 17(10):3077-88. · 7.74 Impact Factor
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ABSTRACT: J Oral Pathol Med (2011) 40: 699–705Background: Insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein, has been implicated in the enhancement of proliferation and invasion in various cancers. This study aimed to investigate the clinical significance and functional role of IGF2BP3 expression in oral squamous cell carcinoma (OSCC).Methods: IGF2BP3 expression in 93 OSCC patients was investigated using immunohistochemical staining and correlated with clinical parameters and patients’ survival. The effect of IGF2BP3 on cell invasion ability was evaluated by RNA interference in OSCC cell line.Results: High expression of IGF2BP3 in OSCC was significantly correlated with large tumor size and lymph node metastasis. Kaplan-Meier analysis revealed that oral cancer patients with high IGF2BP3 expression had a significantly lower 5-year survival (P = 0.0017). Multivariate analysis of clinical samples demonstrated IGF2BP3 to be an independent prognosis factor (P = 0.003). Moreover, the IGF2BP3 shRNA significantly suppressed the invasion ability of OSCC in vitro, and the knockdown of endogenous IGF2BP3 expression also inhibited tumor formation in vivo.Conclusions: IGF2BP3 enhances cell invasion ability and tumorigenicity in human OSCC in vitro and in vivo. IGF2BP3 is an independent prognostic factor in patients with OSCC. Targeting of IGF2BP3 could potentially suppress the tumor growth and metastasis to improve the outcome of patients with OSCC.
Journal of Oral Pathology and Medicine 02/2011; 40(9):699 - 705. · 1.63 Impact Factor
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ABSTRACT: Histone deacetylase 2 (HDAC2) expressions in oral squamous cell carcinoma (OSCC) had been implicated in advanced stage and poor prognosis. It suggests a possible link between the migration/invasion potential of oral cancer cells and the prevalent expression of HDAC2.
Five head and neck cancer (HNC) cell lines, including Ca9-22, Cal-27, HSC-3, SAS, and TW2.6, were used. Cells stably overexpressing HDAC2 and shRNA against HDAC2 were established to investigate migration/invasion ability in vitro and tumorigenesis and progression in vivo.
We found that alterations in the HDAC2 level in OSCC cell lines modulated their invasive ability with a positive correlation. Animal model also showed that knockdown of HDAC2 expression in SAS cells, originally containing high endogenous HDAC2 expression, resulted in decrease in tumor initiation and progression. Using high-throughput transcriptome analysis, numerous genes involved in HIF-1α-associated pathways were found. At the mechanism levels, using agents to block de novo protein synthesis or prevent protein degradation by ubiquitination, we found the stability of hypoxia inducible factor 1α (HIF-1α) protein was maintained in OSCC cells with HDAC2 overexpression. In addition, co-immunoprecipitation assay also revealed that HDAC2-mediated HIF-1α protein stability is because of direct interaction of HIF-1α with von Hippel-Lindau (VHL) protein.
Our work demonstrates that HDAC2 maintains HIF-1α stability, probably at the level of protein modification, which in turn leads to the increase in cell invasion/migration ability in oral cancer progression. These findings implicate the potential of HDAC inhibitors for oral cancer therapy.
Journal of Oral Pathology and Medicine 02/2011; 40(7):567-75. · 1.63 Impact Factor
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Dennis Shin-Shian Hsu,
Hsin-Yi Lan,
Chi-Hung Huang,
Shyh-Kuan Tai,
Shyue-Yih Chang,
Tung-Lung Tsai, Cheng-Chi Chang,
Cheng-Hwai Tzeng,
Kou-Juey Wu,
Jung-Yie Kao,
Muh-Hwa Yang
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ABSTRACT: We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).
The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy.
The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis.
Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells.
Clinical Cancer Research 09/2010; 16(18):4561-71. · 7.74 Impact Factor
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ABSTRACT: To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis.
Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination.
In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor α, interleukin-1β (IL-1β), oncostatin M (OSM), and other IL-6-family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM-induced CREB phosphorylation and CREB-DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM-induced Cyr61 promoter activation was dependent on CRE-CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages.
Simvastatin inhibited cytokine-stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis.
Arthritis & Rheumatism 02/2010; 63(4):1010-20. · 7.87 Impact Factor
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Chiung-Nien Chen, Cheng-Chi Chang,
Ting-En Su,
Wen-Ming Hsu,
Yung-Ming Jeng,
Ming-Chih Ho,
Fon-Jou Hsieh,
Po-Huang Lee,
Min-Liang Kuo,
Hsinyu Lee,
King-Jen Chang
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ABSTRACT: The purpose of this study was to identify genes of interest for a subsequent functional and clinical cohort study using complementary (c)DNA microarrays. cDNA microarray hybridization was performed to identify differentially expressed genes between tumor and nontumor specimens in 30 gastric cancer patients. Subsequent functional studies of the selected gene were carried out, including cell cycle analysis, cell migration analysis, analyses of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF), and oligo-microarray studies using two pairs of stable cell lines of the selected gene. Another independent cohort study of 79 gastric cancer patients was conducted to evaluate the clinical significance of the selected gene in human gastric cancer. Calreticulin (CRT) was selected for further investigation. Two pairs of stable cell lines of CRT overexpression and CRT knockdown were constructed to perform functional studies. CRT enhanced gastric cancer cell proliferation and migration. Overexpressed CRT upregulated the expression and secretion of PlGF and VEGF. CRT had a reciprocal effect on connective tissue growth factor (CTGF) expression. Positive immunohistochemical staining of calreticulin was significantly correlated with high microvessel density (MVD) (p = 0.014), positive serosal invasion (p = 0.013), lymph node metastasis (p = 0.002), perineural invasion (p = 0.008), and poor patient survival (p = 0.0014). Multivariate survival analysis showed that CRT, MVD, and serosal invasion were independent prognosticators. We conclude that CRT overexpression enhances angiogenesis, and facilitates proliferation and migration of gastric cancer cells, which is in line with the association of CRT with MVD, tumor invasion, lymph node metastasis, and survival in gastric cancer patients.
Annals of Surgical Oncology 01/2009; 16(2):524-33. · 4.17 Impact Factor
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ABSTRACT: Breast tumor kinase (Brk), an Src-like nonreceptor tyrosine kinase, is overexpressed in breast cancer and several other cancer types. Our previous study indicates that Brk promotes cell migration and tumor invasion by phosphorylating the focal adhesion protein paxillin. Here, we report the identification of p190RhoGAP-A (p190) as a Brk substrate. Brk phosphorylates p190 at the Y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively. In carcinoma cells expressing high levels of Brk, endogenous Brk functions as a key contributor to epidermal growth factor-induced p190 tyrosine phosphorylation. We present evidence showing that p190 phosphorylation plays essential roles in both migratory and proliferative effects of Brk. Furthermore, disruption of p190 phosphorylation-induced p190/p120 complex in breast cancer cells abolishes not only the abilities of Brk to regulate RhoA and Ras but also the stimulatory effects of Brk on proliferation, migration, invasion, transformation, and tumorigenicity. Together, our findings reveal a previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190 and provide evidence for the crucial roles of this Brk-elicited signaling pathway in promoting breast malignancy.
Cancer Research 11/2008; 68(19):7779-87. · 7.86 Impact Factor
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ABSTRACT: Lysophosphatidic acid (LPA) is a lipid bioactive mediator which binds to G-protein-coupled receptors and activates a variety of cellular functions. LPA modulates multiple behaviors in endothelial cells, including cell proliferation and migration, capillary-like tube formation in vitro, activation of proteases, interactions with leukocytes, and expressions of inflammation-related genes, thereby regulating vessel formation. LPA has been reported to modulate the angiogenesis process. However, the role of LPA in the lymphangiogenesis process has not been studied. In this study, we showed that LPA upregulated vascular endothelial growth factor-C (VEGF-C) mRNA expression in human umbilical vein endothelial cells (HUVECs) and subsequent endothelial cell tube formation in vitro and in vivo. These enhancement effects were LPA(1)- and LPA(3)-dependent and required cyclooxygenase-2 (COX-2), endothelial growth factor receptor (EGFR) transactivation and activation of nuclear factor kappaB (NF-kappaB). Moreover, LPA induced the protein expressions of the lymphatic markers, Prox-1, LYVE-1, and podoplanin, in HUVECs, and these enhancement effects were dependent on LPA(1) and LPA(3) activation and EGFR transactivation. Our results demonstrated that LPA might regulate VEGF-C and lymphatic marker expression in endothelial cells, which contributes to endothelial cell tube formation in vitro and in vivo, thus facilitating endothelial cell participation in the lymphangiogenesis process. This study clarifies the signaling mechanism of LPA-regulated VEGF-C expression and lymphatic marker expressions in endothelial cells, which suggest that LPA may be a suitable target for generating therapeutics against lymphangiogenesis and tumor metastasis.
Cellular Signalling 10/2008; 20(10):1804-14. · 4.06 Impact Factor
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ABSTRACT: Stromal cell-derived factor 1alpha (SDF-1alpha) (CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1alpha (CXCL12)-CXCR4 interaction, exerted during angiogenesis, has not been well understood. We have previously demonstrated that human basal cell carcinoma (BCC) tissues and a BCC cell line (BCC-1/KMC) had significant expression of CXCR4, whose level was higher in invasive than in the non-invasive BCC types. Here, we observed that human BCC tissues with high expression levels of CXCR4 had higher vascularity. Further, among the 71 BCCs diagnosed between the years 2004-2005, BCCs with high CXCR4 expression had concomitantly higher microvessel density, as compared with those with low CXCR4 expression (P < 0.001). We found that SDF-1alpha induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1alpha significantly upregulated several angiogenesis-associated genes such as interferon-alpha-inducible protein 27, interleukin (IL)-6, bone morphogenetic protein (BMP)-6, SOCS2 and cyclooxygenase 2 (COX)-2 in human BCC cells. Among them, IL-6 was the earliest and highest upregulated gene whose induction was observed within 6 h of the commencement of SDF-1alpha-CXCR4 interaction. The mechanisms behind the SDF-1alpha-induced time and dose-dependent upregulation of messenger RNA expression and protein secretion of IL-6 were investigated. The transcriptional regulation of IL-6 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-kappaB complex. The identification of the angiogenic profiles induced through SDF-1alpha-CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1alpha (CXCL12).
Carcinogenesis 10/2008; 30(2):205-13. · 5.70 Impact Factor
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ABSTRACT: Connective tissue growth factor (CTGF) is a member of the CCN family of secreted, matrix-associated proteins encoded by immediate early genes that play various roles in angiogenesis and tumor growth. CCN family proteins share uniform modular structure which mediates various cellular functions such as regulation of cell division, chemotaxis, apoptosis, adhesion, motility, angiogenesis, neoplastic transformation, and ion transport. Recently, CTGF expression has been shown to be associated with tumor development and progression. There is growing body of evidence that CTGF may regulate cancer cell migration, invasion, angiogenesis, and anoikis. In this review, we will highlight the influence of CTGF expression on the biological behavior and progression of various cancer cells, as well as its regulation on various types of protein signals and their mechanisms.
Journal of Biomedical Science 08/2008; 15(6):675-85. · 2.01 Impact Factor
