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2012年7月24日星期二

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases.

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases.

Biochem Soc Trans. 2012 Aug 1;40(4):831-5

Authors: Oltean S, Gammons M, Hulse R, Hamdollah-Zadeh M, Mavrou A, Donaldson L, Salmon AH, Harper SJ, Ladomery MR, Bates DO

Abstract
SRPK1 (serine-arginine protein kinase 1) is a protein kinase that specifically phosphorylates proteins containing serine-arginine-rich domains. Its substrates include a family of SR proteins that are key regulators of mRNA AS (alternative splicing). VEGF (vascular endothelial growth factor), a principal angiogenesis factor contains an alternative 3' splice site in the terminal exon that defines a family of isoforms with a different amino acid sequence at the C-terminal end, resulting in anti-angiogenic activity in the context of VEGF165-driven neovascularization. It has been shown recently in our laboratories that SRPK1 regulates the choice of this splice site through phosphorylation of the splicing factor SRSF1 (serine/arginine-rich splicing factor 1). The present review summarizes progress that has been made to understand how SRPK1 inhibition may be used to manipulate the balance of pro- and anti-angiogenic VEGF isoforms in animal models in vivo and therefore control abnormal angiogenesis and other pathophysiological processes in multiple disease states.

PMID: 22817743 [PubMed - in process]

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Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine.

Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine.

BJU Int. 2012 Jun;109(12):1864-70

Authors: Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Roupr�t M

Abstract
What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti-angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. ? A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. ? RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. ? Alteration of the product of the Von Hippel-Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. ? However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. ? Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. ? Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. ? Recent technological developments, such as large-scale analysis and high-speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.

PMID: 22035299 [PubMed - indexed for MEDLINE]

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2012年7月23日星期一

Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts.

Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts.

Arterioscler Thromb Vasc Biol. 2012 Jul 19;

Authors: Li XD, Chen J, Ruan CC, Zhu DL, Gao PJ

Abstract
OBJECTIVE: Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation. METHODS AND RESULTS: In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis. CONCLUSIONS: These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases.

PMID: 22814749 [PubMed - as supplied by publisher]

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Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.

Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.

Int J Cancer. 2012 Jul 19;

Authors: Szczyrba J, Nolte E, Hart M, D�ll C, Wach S, Taubert H, Keck B, Kremmer E, St�hr R, Hartmann A, Wieland W, Wullich B, Gr�sser FA

Abstract
In primary prostate cancer (PCa), a major cause of cancer-related death in men, the expression of various microRNAs (miRNAs) is deregulated. We previously detected several miRNAs, e.g., miR-24 and miR-22, as significantly down-regulated in PCa (1) . An in silico search predicted that zinc finger protein 217 (ZNF217) and importin 7 (IPO7) were potential target genes of these miRNAs. Additionally, for two genes that are deregulated in PCa (heterogeneous nuclear ribonucleoprotein K, hnRNP-K, and vascular endothelial growth factor A, VEGF-A), we identified two regulatory miRNAs, miR-205 and miR-29b. The regulation of the 3'-untranslated regions (3'UTRs) of the four genes by their respective miRNAs was confirmed by luciferase assays. As expected, the up-regulation of ZNF217, hnRNP-K, VEGF-A and IPO7 could be verified at the protein level in the PCa cell lines LNCaP and DU145. ZNF217 and IPO7, which had not yet been studied in PCa, were analyzed in more detail. ZNF217 mRNA is over-expressed in primary PCa samples, and this overexpression translates to an elevated protein level. However, IPO7 was upregulated at the protein level alone. The inhibition of ZNF217 and IPO7 by siRNA resulted in reduced proliferation of the PCa cell lines. ZNF217 could thus be identified as an oncogene that is overexpressed in PCa and affects the growth of PCa cell lines while the function of IPO7 remains to be elucidated in greater detail. � 2012 Wiley Periodicals, Inc.

PMID: 22815235 [PubMed - as supplied by publisher]

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Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways.

Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways.

Cancer Chemother Pharmacol. 2012 Jul 20;

Authors: Li X, Wang X, Ye H, Peng A, Chen L

Abstract
PURPOSE: We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth. METHODS: Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells. RESULTS: In zebrafish model, 2.5�?mol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways. CONCLUSIONS: These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth.

PMID: 22814678 [PubMed - as supplied by publisher]

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2012年7月22日星期日

First-line chemotherapy in epithelial ovarian cancer.

First-line chemotherapy in epithelial ovarian cancer.

Clin Obstet Gynecol. 2012 Mar;55(1):96-113

Authors: Bookman MA

Abstract
Advanced-stage epithelial ovarian cancer remains a highly lethal malignancy, despite effective cytoreductive surgery and primary chemotherapy. Phase III studies have evaluated multidrug combinations, dose-dense weekly scheduling, intraperitoneal delivery, neoadjuvant chemotherapy, maintenance therapy, and targeting of angiogenesis. Incremental gains in median progression-free or overall survival have been achieved, but without an impact on overall mortality. Data support intraperitoneal cisplatin, dose-dense weekly paclitaxel, or neoadjuvant chemotherapy with interval cytoreduction in appropriate patients. Encouraging data have emerged using antiangiogenic agents, but with questions regarding optimal timing and patient selection. The use of 3-drug combinations or maintenance chemotherapy is not supported.

PMID: 22343232 [PubMed - indexed for MEDLINE]

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Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.

Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.

Clin Exp Nephrol. 2012 Jul 20;

Authors: Chen YT, Cheng BC, Ko SF, Chen CH, Tsai TH, Leu S, Chang HW, Chung SY, Chua S, Yeh KH, Chen YL, Yip HK

Abstract
BACKGROUND: Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1?, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1? in CKD patients. METHODS: The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects. RESULTS: CKD patients had significantly lower numbers of EPCs (p�<�0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p�<�0.001). Compared with patients with early CKD (stages I-III), patients with late CKD [stage IV-V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1? (all p�<�0.01). Serum VEGF level but not MCA or SDF-1? was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p�<�0.04). CONCLUSION: Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs.

PMID: 22814956 [PubMed - as supplied by publisher]

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