Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process
Abstract DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein...
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| Veröffentlicht in: | Cancer letters 2017-07, Vol.398, p.46-51 |
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| creator | Shih, Yi-Ping Yuan, Sarah Y Lo, Su Hao |
| description | Abstract DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis. |
| doi_str_mv | 10.1016/j.canlet.2017.04.004 |
| format | Article |
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Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2017.04.004</identifier><identifier>PMID: 28408355</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Angiogenesis ; Animals ; Aorta ; Cell adhesion & migration ; Cell growth ; Cell migration ; Cell Movement ; Cells, Cultured ; DLC1 ; Down-Regulation ; Endothelial cells ; Endothelial Cells - metabolism ; Epithelial cells ; Focal adhesion ; Genotype ; GTPase-Activating Proteins - deficiency ; GTPase-Activating Proteins - genetics ; GTPase-Activating Proteins - metabolism ; Hematology, Oncology and Palliative Medicine ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Kinases ; Liver cancer ; Mice ; Mice, Knockout ; Neovascularization, Physiologic ; Paxillin ; Paxillin - metabolism ; Phenotype ; rho GTP-Binding Proteins - metabolism ; RhoA ; rhoA GTP-Binding Protein - metabolism ; RhoA protein ; RNA Interference ; Rodents ; Signal Transduction ; Transfection ; Tube formation ; Tumor suppressor genes ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Umbilical vein ; Vascular endothelial growth factor</subject><ispartof>Cancer letters, 2017-07, Vol.398, p.46-51</ispartof><rights>Elsevier B.V.</rights><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier Limited Jul 10, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-3d44d3ffcf21cf6d31900f2d17775d0f56e2500ff257b7ca54a475d64bd0c3883</citedby><cites>FETCH-LOGICAL-c546t-3d44d3ffcf21cf6d31900f2d17775d0f56e2500ff257b7ca54a475d64bd0c3883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2017.04.004$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28408355$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shih, Yi-Ping</creatorcontrib><creatorcontrib>Yuan, Sarah Y</creatorcontrib><creatorcontrib>Lo, Su Hao</creatorcontrib><title>Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Abstract DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Aorta</subject><subject>Cell adhesion & migration</subject><subject>Cell growth</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Cells, Cultured</subject><subject>DLC1</subject><subject>Down-Regulation</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Epithelial cells</subject><subject>Focal adhesion</subject><subject>Genotype</subject><subject>GTPase-Activating Proteins - deficiency</subject><subject>GTPase-Activating Proteins - genetics</subject><subject>GTPase-Activating Proteins - metabolism</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Human Umbilical Vein Endothelial Cells - metabolism</subject><subject>Humans</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neovascularization, Physiologic</subject><subject>Paxillin</subject><subject>Paxillin - metabolism</subject><subject>Phenotype</subject><subject>rho GTP-Binding Proteins - metabolism</subject><subject>RhoA</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>RhoA protein</subject><subject>RNA Interference</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Transfection</subject><subject>Tube formation</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Umbilical vein</subject><subject>Vascular endothelial growth factor</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUk1v1DAQjRCILoV_gFAkLlwSxrEdJxcktOVLWgkh4Gx57fHWi9de7KSo_x5HW1rohZOlmTdv3vObqnpOoCVA-tf7VqvgcWo7IKIF1gKwB9WKDKJrxDjAw2oFFFhDB8rPqic57wGAM8EfV2fdwKCU-ar6chF_hSbhbvZqcjHU0dYXmzWpXagxmDhdonfK1xq9z7WOh2OKB5cx16VTq7BzcYcBs8t16WjM-Wn1yCqf8dnNe159f__u2_pjs_n84dP67abRnPVTQw1jhlqrbUe07Q0lI4DtDBFCcAOW99jxUrEdF1uhFWeqaDc92xrQdBjoefXmxHuctwc0GsOUlJfH5A4qXcuonPy3E9yl3MUrWdbDOHSF4NUNQYo_Z8yTLMYWnypgnLMkwzD0RQxfdr28B93HOYVir6BGzsax52NBsRNKp5hzQnsrhoBcMpN7ecpMLplJYLJkVsZe_G3kduhPSHdOsXznlcMks3YYNBqXUE_SRPe_DfcJtHfBaeV_4DXmOy8ydxLk1-VulrMhgkJHGaW_Ad9_v1I</recordid><startdate>20170710</startdate><enddate>20170710</enddate><creator>Shih, Yi-Ping</creator><creator>Yuan, Sarah Y</creator><creator>Lo, Su Hao</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170710</creationdate><title>Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process</title><author>Shih, Yi-Ping ; Yuan, Sarah Y ; Lo, Su Hao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c546t-3d44d3ffcf21cf6d31900f2d17775d0f56e2500ff257b7ca54a475d64bd0c3883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Aorta</topic><topic>Cell adhesion & migration</topic><topic>Cell growth</topic><topic>Cell migration</topic><topic>Cell Movement</topic><topic>Cells, Cultured</topic><topic>DLC1</topic><topic>Down-Regulation</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Epithelial cells</topic><topic>Focal adhesion</topic><topic>Genotype</topic><topic>GTPase-Activating Proteins - deficiency</topic><topic>GTPase-Activating Proteins - genetics</topic><topic>GTPase-Activating Proteins - metabolism</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Human Umbilical Vein Endothelial Cells - metabolism</topic><topic>Humans</topic><topic>Kinases</topic><topic>Liver cancer</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neovascularization, Physiologic</topic><topic>Paxillin</topic><topic>Paxillin - metabolism</topic><topic>Phenotype</topic><topic>rho GTP-Binding Proteins - metabolism</topic><topic>RhoA</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>RhoA protein</topic><topic>RNA Interference</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Transfection</topic><topic>Tube formation</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Umbilical vein</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shih, Yi-Ping</creatorcontrib><creatorcontrib>Yuan, Sarah Y</creatorcontrib><creatorcontrib>Lo, Su Hao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shih, Yi-Ping</au><au>Yuan, Sarah Y</au><au>Lo, Su Hao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2017-07-10</date><risdate>2017</risdate><volume>398</volume><spage>46</spage><epage>51</epage><pages>46-51</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Abstract DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. 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| ispartof | Cancer letters, 2017-07, Vol.398, p.46-51 |
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| language | eng |
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| subjects | Angiogenesis Animals Aorta Cell adhesion & migration Cell growth Cell migration Cell Movement Cells, Cultured DLC1 Down-Regulation Endothelial cells Endothelial Cells - metabolism Epithelial cells Focal adhesion Genotype GTPase-Activating Proteins - deficiency GTPase-Activating Proteins - genetics GTPase-Activating Proteins - metabolism Hematology, Oncology and Palliative Medicine Human Umbilical Vein Endothelial Cells - metabolism Humans Kinases Liver cancer Mice Mice, Knockout Neovascularization, Physiologic Paxillin Paxillin - metabolism Phenotype rho GTP-Binding Proteins - metabolism RhoA rhoA GTP-Binding Protein - metabolism RhoA protein RNA Interference Rodents Signal Transduction Transfection Tube formation Tumor suppressor genes Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Umbilical vein Vascular endothelial growth factor |
| title | Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process |
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