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Rui Xu

Bio: Rui Xu is an academic researcher from Nanjing Medical University. The author has contributed to research in topics: MAPK/ERK pathway & Wnt signaling pathway. The author has an hindex of 7, co-authored 7 publications receiving 311 citations.

Papers
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Journal ArticleDOI
Jun Du1, Rui Xu1, Zhenzhen Hu1, Yinhui Tian1, Yichao Zhu1, Luo Gu1, Lei Zhou1 
27 Sep 2011-PLOS ONE
TL;DR: It is demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.
Abstract: Background Hypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown. Methodology/Principal Findings In this study, we reported that hypoxia could induce HIF-1α and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1α and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1α expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1α expression. Conclusions/Significance Taken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.

93 citations

Journal ArticleDOI
TL;DR: It is demonstrated for the first time that Wnt5a promoted gastric cancer cell migration via the PI3K/Akt/GSK3β/RhoA signaling pathway.

79 citations

Journal ArticleDOI
TL;DR: It is shown that Wnt5a dose dependently activated Dvl2, Rab35 and Rac1 and subsequently promoted the migration of MCF-7 cells, which was, however, abolished by knocking down Wnt 5a expression via small interfering RNA (siRNA) transfection.

52 citations

Journal ArticleDOI
TL;DR: It is shown that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells, and a novel Arf6/ERK signaling pathway is identified for E GF-regulated Wnt 5a expression at transcriptional level of Gastric cancer cells.
Abstract: Wnt5a, a ligand for activating the non-canonical Wnt signaling pathway, is commonly associated with Epithelial-to-mesenchymal transition (EMT) in cancer cell metastasis. Here, we show that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells. To further explore the mechanisms, we investigated the effect of EGF signaling on Wnt5a expression. EGF increased Arf6 and ERK activity, while blockade of Arf6 activation repressed ERK activity, up-regulated Wnt5a expression and repressed EMT in response to EGF. We also demonstrate that EGF inactivated Wnt5a transcription by direct recruitment of ERK to the Wnt5a promoter. On the other hand, inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus, following rescued Wnt5a mRNA and protein expression and favored an epithelial phenotype of SGC-7901 cells. In addition, we notice that kinase-dead, nuclear-localised ERK has inhibitory effect on Wnt5a transcription. Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5a protein levels and an association between Wnt5a expression and better prognosis. These findings indicate that Wnt5a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5a expression at transcriptional level of gastric cancer cells.

52 citations

Journal ArticleDOI
TL;DR: Melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation and that of the PI3k/Akt signaling pathway.
Abstract: Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation.

28 citations


Cited by
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Journal ArticleDOI
TL;DR: Insight is provided on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF‐1a regulation and the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process.
Abstract: Hypoxia-Inducible Factor-1 (HIF-1) has been largely studied for its role in cell survival in hypoxic conditions. The regulation of HIF-1 is a complex process and involves a number of molecules and pathways. Among these mechanisms a direct regulatory role of reactive oxygen species (ROS) on HIF-1 alpha subunit has received a great deal of attention and the existing body of literature includes many contradictory findings. Other intermediates such as nitric oxide (NO), specific microRNAs (miR), and transcriptional and post-translational modification have also been implicated as players in ROS mediated HIF-1a regulation. The focus of this review is to present the past conflicting evidence along with more recent findings in order to relate various aspects of this complex process. Aside from the direct role of ROS on HIF-1a regulation under hypoxia and normoxia, we analyzed the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process. We also present findings on transcriptional and translational regulation of HIF-1a via ROS and the interplay with microRNAs in this process. This review further provides insight on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF-1a regulation. Ultimately further research and discovery regarding HIF-1 regulation by oxidative stress is warranted for better understanding of disease development and potential therapeutics for pathologies such as cancer, inflammatory diseases, and ischemia-reperfusion injury.

327 citations

Journal Article
TL;DR: Investigating potential mechanisms modulating GC cell EMT and discovering novel EMT regulators will further elucidate GC biology, and may provide new biomarkers for early GC detection and potentially efficient targets for preventative and curative anti-GC intervention approaches to prevent local and distant invasions.
Abstract: Gastric cancer (GC) is one of the most common malignancies worldwide with poor prognosis for lack of early detection and effective treatment modalities. The significant influence of tumor microenvironment on malignant cells has been extensively investigated in this targeted-therapy era. Epithelial-mesenchymal transition (EMT) is a highly conserved and fundamental process that is critical for embryogenesis and some other pathophysiological processes, especially tumor genesis and progression. Aberrant gastric EMT activation could endow gastric epithelial cells with increased mesenchymal characteristics and less epithelial features, and promote cancer cell stemness, initiation, invasion, metastasis, and chemo-resistance with cellular adhesion molecules especially E-cadherin concomitantly repressed, which allows tumor cells to disseminate and spread throughout the body. Some pathogens, stress, and hypoxia could induce and aggravate GC via EMT, which is significantly correlated with prognosis. GC EMT is modulated by diverse micro-environmental, membrane, and intracellular cues, and could be triggered by various overexpressed transcription factors, which are downstream of several vital cross-talking signaling pathways including TGF-β, Wnt/β-catenin, Notch, etc. microRNAs also contribute significantly to GC EMT modulation. There are currently some agents which could suppress GC EMT, shedding light on novel anti-malignancy strategies. Investigating potential mechanisms modulating GC cell EMT and discovering novel EMT regulators will further elucidate GC biology, and may provide new biomarkers for early GC detection and potentially efficient targets for preventative and curative anti-GC intervention approaches to prevent local and distant invasions.

217 citations

01 Nov 2015
TL;DR: In this article, the authors proposed a new method for cancer drug discovery based on protein-protein interactions, and obtained grants from the National Institutes of Health (U.S.) (Grants 54CA126513, R01CA093405, R1CA120979, and R1DK052778).
Abstract: National Institutes of Health (U.S.) (Grants 54CA126513, R01CA093405, R01CA120979, and R01DK052778)

185 citations

Journal ArticleDOI
26 Aug 2016-Cancers
TL;DR: Findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types are reviewed, and Wnt 5a in ovarian cancer is highlighted.
Abstract: Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer.

181 citations