| 1. |
- Al-Haidari, Amr A., et al.
(författare)
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MiR-155-5p positively regulates CCL17-induced colon cancer cell migration by targeting RhoA
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:9, s. 14887-14896
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is the second most common cause of cancer-related death, which is due to migration of tumor cells to distant sites of metastasis. Accumulating data indicate that mciroRNAs play an important role in several aspects of colon cancer cell biology. Herein, we examined the role of miR-155-5p in colon cancer cell migration induced by the CCL17-CCR4 axis in HT-29 colon cancer cells. We found that miR-155-5p knockdown in serum starved colon cancer cells decreased CCL17-induced cell chemotaxis. Moreover, knocking down miR-155-5p markedly decreased CCL17-provoked activation of RhoA in colon cancer cells. Bioinformatics analysis predicted two putative binding sites in the AU-rich element at the 3'-UTR of RhoA mRNA. MiR-155-5p binding to RhoA mRNA was verified using a target site blocker and functionally validated by RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of RhoA mRNA is mediated by AU-rich elements present in the 3'-UTR region. Taken together, these results show that miR-155-5p positively regulates RhoA mRNA levels and translation as well as cell migration in serum starved colon cancer cells and indicate that targeting miR-155-5p might be a useful strategy to antagonize colon cancer metastasis.
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| 2. |
- Al-Haidari, Amr, et al.
(författare)
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MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R (HuR)
- 2018
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 421, s. 145-151
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the worst prognostic factor for patients with CRC. HuR (ELAVL1) is overexpressed in CRC and has been reported to promote colon cancer growth by targeting RNA in the cell cytoplasm. Herein, the role of miR-155-5p in regulating HuR expression and cell migration was examined in colon cancer cells. MiR-155-5p knockdown in serum-starved colon cancer cells decreased both colon cancer cell chemotaxis and cytoplasmic expression of HuR. Bioinformatics analysis predicted two putative binding sites in the AU-rich elements (AREs) at the 3′-UTR of HuR mRNA. MiR-155-5p binding to HuR was verified using specific target site blockers and functionally validated by use of RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of HuR expression is mediated by AREs. Targeting AREs with a specific blocker inhibited colon cancer cell migration. Taken together, these novel findings demonstrate that AREs mediate miR-155-5p positive regulation of HuR mRNA levels and translation as well as migration in colon cancer cells, suggesting that targeting miR-155-5p and/or Hur might be useful therapeutic strategies against colon cancer metastasis.
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| 3. |
- Al-Haidari, Amr, et al.
(författare)
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Neutrophil extracellular traps promote surgery-induced peritoneal carcinosis of metastatic colorectal cancer via modulation of CXCR2 and αv integrin
- 2017. - Suppl 3
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 28, s. 87-88
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Konferensbidrag (refereegranskat)abstract
- Introduction: Peritoneal carcinosis (PC) is the third common site of metastatic colorectal cancer which characterized by a very low survival rate. Surgical trauma has been identified as an important factor in the progression of PC, postulated to be caused by the inflammatory response to tissue injury. The mechanism behind tumor metastasis remains poorly understood. However, existing evidence indicates that neutrophils, via Neutrophil Extracellular Traps (NETs), are implicated in the development of metastatic disease and recently identified as one of the most significant key players in promoting tumor progression. In this study, we highlight the mechanism by which NETs promote surgery-induced colon cancer cell peritoneal metastasis through regulation of key receptors, CXCR2 and αvβ3 integrin.Methods: We developed a murine model of surgical stress-induced PC by post-surgery inoculation of CT-26 murine colon cancer cell line. Surface expression of CXCR2 and αvβ3 on CT-26 cells were evaluated by flow cytometry live staining. Gene expression of extracellular matrix (ECM) proteins from wound incision wall was quantified using qRT-PCR. Function of CXCR2 and αvβ3 in tumor cell migration, proliferation, and adhesion were assessed by blocking assays using CXCR2 antagonist SB225002 and anti-CD51 in vitro and in vivo. Role of neutrophils in promoting cancer cell migration and adhesion was demonstrated using in vitro co-cultured migration and adhesion assays. NET formation was measured using modified ELISA technique of Histone-DNA complex. Depletion of NETs were achieved by daily intraperitoneal administration of 2mg/kg DNase I to mice for 10 days and tumor growth was evaluated by counting macroscopic nodules number on the peritoneum.Results: Blocking CXCR2 and Targeting αv integrin reduced tumor nodules number in vivo by 70% and 65% respectively and decreased cancer cell migration, proliferation, and adhesion in vitro. Incision wound tissue displayed pronounced reduction in ECM proteins mRNAs in treated mice with both CXCR2 antagonist and αv antibody. Mice treatment with DNase I significantly reduced tumor nodules number more than 90% compared to tumor control. Anti-CD51 decreased NET-induced CT-26 cell adhesion. Neutrophils stimulation with MIP-2 exhibits dose-dependent increase of NETosis. Co-culture of neutrophils and cancer cells provoked NETs formation and increased capacity of colon cancer cell migration while DNase I treatment abolished neutrophils NETs-induced tumor cell migration in vitroConclusion: Our novel findings implicate NETs in the development of PC due to surgical stress, suggesting that blocking NET formation might be an interesting potential therapeutic approach.
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| 4. |
- Changhui, Yu, et al.
(författare)
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Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 746, s. 245-251
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil recruitment is known to be a rate-limiting step in mediating tissue injury in severe acute pancreatitis (AP). However, the signalling mechanisms controlling inflammation and organ damage in AP remain elusive. Herein, we examined the role of Ras signalling in AP. Male C57BL/6 mice were treated with a Ras inhibitor (farnesylthiosalicylic acid, FTS) before infusion of taurocholate into the pancreatic duct. Pancreatic and lung tissues as well as blood were collected 24h after pancreatitis induction. Pretreatment with FTS decreased serum amylase levels by 82% and significantly attenuated acinar cell necrosis, tissue haemorrhage and oedema formation in taurocholate-induced pancreatitis. Inhibition of Ras signalling reduced myeloperoxidase (MPO) levels in the inflamed pancreas by 42%. In addition, administration of FTS decreased pancreatic levels of CXC chemokines as well as circulating levels of interleukin-6 and high-mobility group box 1 in animals exposed to taurocholate. Moreover, treatment with FTS reduced taurocholate-induced MPO levels in the lung. Inhibition of Ras signalling had no effect on neutrophil expression of Mac-1 in mice with pancreatitis. Moreover, FTS had no direct impact on trypsin activation in isolated pancreatic acinar cells. These results indicate that Ras signalling controls CXC chemokine formation, neutrophil recruitment and tissue injury in severe AP. Thus, our findings highlight a new signalling mechanism regulating neutrophil recruitment in the pancreas and suggest that inhibition of Ras signalling might be a useful strategy to attenuate local and systemic inflammation in severe AP.
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| 5. |
- Changhui, Yu, et al.
(författare)
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Platelet-Derived CCL5 Regulates CXC Chemokine Formation and Neutrophil Recruitment in Acute Experimental Colitis.
- 2016
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 231:2, s. 370-376
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating data suggest that platelets not only regulate thrombosis and haemostasis but also inflammatory processes. Platelets contain numerous potent pro-inflammatory compounds, including the chemokines CCL5 and CXCL4 although their role in acute colitis remains elusive. The aim of this study was to examine the role of platelets and platelet-derived chemokines in acute colitis. Acute colitis was induced in female Balb/c mice by administration of 5% dextran sodium sulphate (DSS) for five days. Animals received a platelet-depleting, anti-CCL5, anti-CXCL4 or a control antibody prior to DSS challenge. Colonic tissue was collected for quantification of myeloperoxidase (MPO) activity, CXCL5, CXCL2, interleukin-6 (IL-6) and CCL5 levels as well as morphological analyses. Platelet depletion reduced tissue damage and clinical disease activity index in DSS-exposed animals. Platelet depletion not only reduced levels of CXCL2 and CXCL5 but also levels of CCL5 in the inflamed colon. Immunoneutralization of CCL5 but not CXCL4 reduced tissue damage, CXC chemokine expression and neutrophil recruitment in DSS-treated animals. These findings show that platelets play a key role in acute colitis by regulating CXC chemokine generation, neutrophil infiltration and tissue damage in the colon. Moreover, our results suggest that platelet-derived CCL5 is an important link between platelet activation and neutrophil recruitment in acute colitis. This article is protected by copyright. All rights reserved.
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| 6. |
- Du, Feifei, et al.
(författare)
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Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo
- 2019
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Ingår i: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 60:1-2, s. 53-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
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| 7. |
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| 8. |
- Hawez, Avin, et al.
(författare)
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MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation of NETs. Bone marrow neutrophils were stimulated with PMA and MIP-2. Pre-incubation of neutrophils with translational inhibitors (cycloheximide or puromycin) markedly decreased NET formation induced by PMA or MIP-2. Neutrophil transfection with a mimic miR-155 increased PMA-induced PAD4 mRNA expression and NET formation. In contrast, transfection with an antagomiR-155 decreased induction of PAD4 mRNA and NETs in response to PMA challenge. Bioinformatical examination of PAD4 revealed a potential binding site in AU-rich elements at the 3′-UTR region. MiR-155 binding to PAD4 was examined by use of target site blockers and RNA immunoprecipitation, revealing that miR-155 regulation of PAD4 mRNA is mediated via AU-rich elements in the 3′-UTR region. In conclusion, our findings demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel results indicate that targeting miR-155 might be useful to inhibit exaggerated NET generation in inflammatory diseases.
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| 9. |
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| 10. |
- Hwaiz, Rundk, et al.
(författare)
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Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury.
- 2015
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 97:5, s. 975-984
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggest that platelets play an important role in regulating neutrophil recruitment in septic lung injury. Herein, we hypothesized that platelet-derived CCL5 might facilitate sepsis-induced neutrophil accumulation in the lung. Abdominal sepsis was induced by CLP in C57BL/6 mice. CLP increased plasma levels of CCL5. Platelet depletion and treatment with the Rac1 inhibitor NSC23766 markedly reduced CCL5 in the plasma of septic mice. Moreover, Rac1 inhibition completely inhibited proteasePAR4-induced secretion of CCL5 in isolated platelets. Immunoneutralization of CCL5 decreased CLP-induced neutrophil infiltration, edema formation, and tissue injury in the lung. However, inhibition of CCL5 function had no effect on CLP-induced expression of Mac-1 on neutrophils. The blocking of CCL5 decreased plasma and lung levels of CXCL1 and CXCL2 in septic animals. CCL5 had no effect on neutrophil chemotaxis in vitro, suggesting an indirect effect of CCL5 on neutrophil recruitment. Intratracheal challenge with CCL5 increased accumulation of neutrophils and formation of CXCL2 in the lung. Administration of the CXCR2 antagonist SB225002 abolished CCL5-induced pulmonary recruitment of neutrophils. Isolated alveolar macrophages expressed significant levels of the CCL5 receptors CCR1 and CCR5. In addition, CCL5 triggered significant secretion of CXCL2 from isolated alveolar macrophages. Notably, intratracheal administration of clodronate not only depleted mice of alveolar macrophages but also abolished CCL5-induced formation of CXCL2 in the lung. Taken together, our findings suggest that Rac1 regulates platelet secretion of CCL5 and that CCL5 is a potent inducer of neutrophil recruitment in septic lung injury via formation of CXCL2 in alveolar macrophages.
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