Focal adhesion kinase signaling pathway participates in the formation of choroidal neovascularization and regulates the proliferation and migration of choroidal microvascular endothelial cells by acting through HIF-1 and VEGF expression in RPE cells

Zhu, Jie; Wang, Yusheng; Zhang, Jian; Zhao, Wei; Xiao-sheng, Yang; Li, Xia; Jiang, Tongtong; Yao, Libo

doi:10.1016/j.exer.2008.11.034

Cited by 42 publications

(40 citation statements)

References 54 publications

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“…In addition, focal adhesion kinase ( FAK ), a part of the focal adhesion pathway, plays a functionally significant role in ovarian cancer migration and invasion [35]. These two cooperating pathways are thought to be important in the mechanisms of complex tumorigenesis in ovarian cancer since focal adhesion kinase signaling pathway regulates the proliferation and migration of choroidal microvascular endothelial cells by acting through HIF - 1 expression [36]. In addition, we found possible interactions between GO gene sets associated with ovarian cancer stage: “cell surface binding” and “golgi lumen”.…”

Section: Resultsmentioning

confidence: 99%

Knowledge-driven genomic interactions: an application in ovarian cancer

Kim

Dudek

et al. 2014

BioData Mining

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BackgroundEffective cancer clinical outcome prediction for understanding of the mechanism of various types of cancer has been pursued using molecular-based data such as gene expression profiles, an approach that has promise for providing better diagnostics and supporting further therapies. However, clinical outcome prediction based on gene expression profiles varies between independent data sets. Further, single-gene expression outcome prediction is limited for cancer evaluation since genes do not act in isolation, but rather interact with other genes in complex signaling or regulatory networks. In addition, since pathways are more likely to co-operate together, it would be desirable to incorporate expert knowledge to combine pathways in a useful and informative manner.MethodsThus, we propose a novel approach for identifying knowledge-driven genomic interactions and applying it to discover models associated with cancer clinical phenotypes using grammatical evolution neural networks (GENN). In order to demonstrate the utility of the proposed approach, an ovarian cancer data from the Cancer Genome Atlas (TCGA) was used for predicting clinical stage as a pilot project.ResultsWe identified knowledge-driven genomic interactions associated with cancer stage from single knowledge bases such as sources of pathway-pathway interaction, but also knowledge-driven genomic interactions across different sets of knowledge bases such as pathway-protein family interactions by integrating different types of information. Notably, an integration model from different sources of biological knowledge achieved 78.82% balanced accuracy and outperformed the top models with gene expression or single knowledge-based data types alone. Furthermore, the results from the models are more interpretable because they are framed in the context of specific biological pathways or other expert knowledge.ConclusionsThe success of the pilot study we have presented herein will allow us to pursue further identification of models predictive of clinical cancer survival and recurrence. Understanding the underlying tumorigenesis and progression in ovarian cancer through the global view of interactions within/between different biological knowledge sources has the potential for providing more effective screening strategies and therapeutic targets for many types of cancer.

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Section: Resultsmentioning

confidence: 99%

Knowledge-driven genomic interactions: an application in ovarian cancer

Kim

Dudek

et al. 2014

BioData Mining

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“…The present direct demonstration of the attenuation of FAK phosphorylation by HIF-1␣ or VEGF siRNA suggests that focal adhesion is altered in response to HIF-1␣ and VEGF expression. Recently, FAK silencing has been linked with inhibition of hypoxia-induced HIF-1␣ and VEGF, indicating an involvement of FAK-dependent signaling pathway in the evolution of hypoxia-induced HIF-1 stabilization and VEGF expression in retinal pigment epithelial cells (35). So, FAK might lie both upstream and downstream of HIF-1, which is dependent on the cell types, maturity, and environmental conditions.…”

Section: Discussionmentioning

confidence: 98%

Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways

Lee

Song

Ahn

et al. 2010

American Journal of Physiology-Cell Physiology

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Here we show that the effect of hypoxia on human umbilical cord blood mesenchymal stem cell (hMSC) migration is via the modulation of focal adhesion kinase (FAK) and its related signaling pathways. Hypoxia increased hMSC migration and cell viability, whereas lactate dehydrogenase (LDH) release was not affected for up to 48 h (data not shown). In addition, hypoxia increased the level of reactive oxygen species (ROS) generation in a time-dependent manner. Hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) were inhibited by the antioxidant (N-acetylcysteine, NAC, 10(-6) M) and (taurine, 4x10(-6) M). Hypoxia-induced endothelial nitric oxide synthase (eNOS) phosphorylation was regulated by p38 MAPK and SAPK/JNK activation. In addition, hypoxia increased the level of hypoxia inducible factor (HIF)-1alpha expression, which was blocked by inhibition of eNOS. Also, hypoxia-induced expression of Flk-1, vascular endothelial growth factor (VEGF), and its secreted form were inhibited by HIF-1alpha small interfering RNA (siRNA). In this hypoxic condition, FAK and Src phosphorylation were increased in a time-dependent manner. Inhibition of Src with specific inhibitor (PP2, 10(-8) M) blocked hypoxia-induced FAK activation. Subsequently, hypoxia-induced FAK phosphorylation was blocked by VEGF siRNA. Finally, hypoxia-induced increase of hMSC migration was inhibited by FAK siRNA. The results indicate that hypoxia increases migration of hMSCs via VEGF-mediated FAK phospholylation and involves the cooperative activity of the ROS, MAPK, eNOS and HIF-1alpha pathways.

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“…15,16 Previous reports showed that integrin ␣5␤1 expression increased dramatically in vascular endothelial cells treated with growth factor in vitro 17 and in laser-induced CNV lesions in rats and mice. 18 The results of a phase II clinical trial in which cancer patients were treated intravenously with the integrin ␣5␤1 inhibitor volociximab suggest that integrin ␣5␤1 inhibition has remarkable antiangiogenic efficacy.…”

Section: Purposementioning

confidence: 98%