Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α-Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

Julovi, Sohel M.; Shen, Kaitlin; McKelvey, Kelly; Minhas, Nikita; March, Lyn; Jackson, Chris

doi:10.2119/molmed.2013.00034

Cited by 10 publications

(9 citation statements)

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“…It has been suggested that several signaling molecules, such as Akt and MAPKs, including p38, JNK, and ERK1/2, participate in controlling cell invasion (Julovi et al, ). In the present study, we found that EG‐VEGF facilitates trophoblast cell invasiveness, and we explored the downstream signaling in EG‐VEGF‐treated trophoblast cells.…”

Section: Resultsmentioning

confidence: 99%

Primary Cilium‐Regulated EG‐VEGF Signaling Facilitates Trophoblast Invasion

Wang

Tsai

Syu

et al. 2016

Journal Cellular Physiology

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Trophoblast invasion is an important event in embryo implantation and placental development. During these processes, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is the key regulator mediating the crosstalk at the feto-maternal interface. The primary cilium is a cellular antenna receiving environmental signals and is crucial for proper development. However, little is known regarding the role of the primary cilium in early human pregnancy. Here, we demonstrate that EG-VEGF regulates trophoblast cell invasion via primary cilia. We found that EG-VEGF activated ERK1/2 signaling and subsequent upregulation of MMP2 and MMP9, thereby facilitating cell invasion in human trophoblast HTR-8/SVneo cells. Inhibition of ERK1/2 alleviated the expression of MMPs and trophoblast cell invasion after EG-VEGF treatment. In addition, primary cilia were observed in all the trophoblast cell lines tested and, more importantly, in human first-trimester placental tissue. The receptor of EG-VEGF, PROKR1, was detected in primary cilia. Depletion of IFT88, the intraflagellar transporter required for ciliogenesis, inhibited primary cilium growth, thereby ameliorating ERK1/2 activation, MMP upregulation, and trophoblast cell invasion promoted by EG-VEGF. These findings demonstrate a novel function of primary cilia in controlling EG-VEGF-regulated trophoblast invasion and reveal the underlying molecular mechanism. J. Cell. Physiol. 232: 1467-1477, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Primary Cilium‐Regulated EG‐VEGF Signaling Facilitates Trophoblast Invasion

Wang

Tsai

Syu

et al. 2016

Journal Cellular Physiology

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“…These findings suggest a role of APC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration (Bezuhly et al , 2009). In addition, it is reported that APC induces enhanced expression of p21 WAF1/CIP1 and p27 KIP1 in rheumatoid synovial fibroblasts (Julovi et al , 2013). As aforementioned, p21 WAF1/CIP1+ liver cell foci were increased after 4 weeks of TAA-promotion, and p21 WAF1/CIP1– liver cell foci were increased after 8 weeks of TAA-promotion (Tsuchiya et al , 2012), suggesting that APC plays a role in the facilitation of cellular senescence in liver cells, and its downregulation directs liver cells to begin the carcinogenic process.…”

Section: Discussionmentioning

confidence: 99%

“…As aforementioned, p21 WAF1/CIP1+ liver cell foci were increased after 4 weeks of TAA-promotion, and p21 WAF1/CIP1– liver cell foci were increased after 8 weeks of TAA-promotion (Tsuchiya et al , 2012), suggesting that APC plays a role in the facilitation of cellular senescence in liver cells, and its downregulation directs liver cells to begin the carcinogenic process. In addition, it is also reported that APC downregulates tumor necrosis factor α-stimulated cell proliferation and activation of p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase and AKT in rheumatoid synovial fibroblasts (Julovi et al , 2013). We previously found an increase of liver cell foci expressing AKT-signaling molecules and activated p38 MAPK by phosphorylation in a population of GST-P + foci produced by promotion with nongenotoxic hepatocarcinogens (Ichimura et al , 2010; Taniai et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

Expression Characteristics of Genes Hypermethylated and Downregulated in Rat Liver Specific to Nongenotoxic Hepatocarcinogens

Ito

Nakajima

Masubuchi

et al. 2019

Toxicological Sciences

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This study examined hypermethylated and downregulated genes specific to carbon tetrachloride (CCl 4 ) by Methyl-Seq analysis combined with expression microarray analysis in the liver of rats treated with CCl 4 or N- nitrosodiethylamine (DEN) for 28 days, by excluding those with DEN. Among 52 genes, Ldlrad4 , Proc , Cdh17 , and Nfia were confirmed to show promoter-region hypermethylation by methylation-specific quantitative PCR analysis on day 28. The transcript levels of these 4 genes decreased by real-time reverse transcription-PCR analysis in the livers of rats treated with nongenotoxic hepatocarcinogens for up to 90 days compared with untreated controls and genotoxic hepatocarcinogens. Immunohistochemically, LDLRAD4 and PROC showed decreased immunoreactivity, forming negative foci, in glutathione S -transferase placental form (GST-P) + foci, and incidences of LDLRAD4 − and PROC − foci in GST-P + foci induced by treatment with nongenotoxic hepatocarcinogens for 84 or 90 days were increased compared with those with genotoxic hepatocarcinogens. In contrast, CDH17 and NFIA responded to hepatocarcinogens without any relation to the genotoxic potential of carcinogens. All 4 genes did not respond to renal carcinogens after treatment for 28 days. Considering that Ldlrad4 is a negative regulator of transforming growth factor-β signaling, Proc participating in p21 WAF1/CIP1 upregulation by activation, Cdh17 inducing cell cycle arrest by gene knockdown, and Nfia playing a role in a tumor-suppressor, all these genes may be potential in vivo epigenetic markers of nongenotoxic hepatocarcinogens from the early stages of treatment in terms of gene expression changes. LDLRAD4 and PROC may have a role in the development of preneoplastic lesions produced by nongenotoxic hepatocarcinogens.

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“…Primary tumour cell cultures were established by explant growth of small fragments (≈1 mm) dissected from the PDAC tumour tissues, placed in DMEM (pH7.4) supplemented with 10% heat-inactivated FBS with 50 units/ml penicillin/streptomycin. Cultures were used after passage 3 to avoid residual contamination by macrophages [ 30 ]. All cultures were collected under identical growth and serum conditions.…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein A-II Plus Lipid Emulsion Enhance Cell Growth via SR-B1 and Target Pancreatic Cancer In Vitro and In Vivo

Julovi

Xue

et al. 2016

PLoS ONE

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BackgroundApolipoprotein A-II (ApoA-II) is down regulated in the sera of pancreatic ductal adenocarcinoma (PDAC) patients, which may be due to increase utilization of high density lipoprotein (HDL) lipid by pancreatic cancer tissue. This study examined the influence of exogenous ApoA-II on lipid uptake and cell growth in pancreatic cancer (PC) both in vitro and in vivo.MethodsCryo transmission electron microscopy (TEM) examined ApoA-II’s influence on morphology of SMOFLipid emulsion. The influence of ApoA-II on proliferation of cancer cell lines was determined by incubating them with lipid+/-ApoA-II and anti-SR-B1 antibody. Lipid was labeled with the fluorophore, DiD, to trace lipid uptake by cancer cells in vitro by confocal microscopy and in vivo in PDAC patient derived xenograft tumours (PDXT) by fluorescence imaging. Scavenger receptor class B type-1(SR-B1) expression in PDAC cell lines and in PDAC PDXT was measured by western blotting and immunohistochemistry, respectively.ResultsApoA-II spontaneously converted lipid emulsion into very small unilamellar rHDL like vesicles (rHDL/A-II) and enhanced lipid uptake in PANC-1, CFPAC-1 and primary tumour cells as shown by confocal microscopy. SR-B1 expression was 13.2, 10.6, 3.1 and 2.3 fold higher in PANC-1, MIAPaCa-2, CFPAC-1 and BxPC3 cell lines than the normal pancreatic cell line (HPDE6) and 3.7 fold greater in PDAC tissue than in normal pancreas. ApoA-II plus lipid significantly increased the uptake of labeled lipid and promoted cell growth in PANC-1, MIAPaCa-2, CFPAC-1 and BxPC3 cells which was inhibited by anti SR-B1 antibody. Further, ApoA-II increased the uptake of lipid in xenografts by 3.4 fold.ConclusionOur data suggest that ApoA-II enhance targeting potential of lipid in pancreatic cancer which may have imaging and drug delivery potentialities.

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Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α-Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

Cited by 10 publications

References 70 publications

Primary Cilium‐Regulated EG‐VEGF Signaling Facilitates Trophoblast Invasion

Primary Cilium‐Regulated EG‐VEGF Signaling Facilitates Trophoblast Invasion

Expression Characteristics of Genes Hypermethylated and Downregulated in Rat Liver Specific to Nongenotoxic Hepatocarcinogens

Apolipoprotein A-II Plus Lipid Emulsion Enhance Cell Growth via SR-B1 and Target Pancreatic Cancer In Vitro and In Vivo

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