NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways
Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is...
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| Veröffentlicht in: | Journal of cellular physiology 2019-02, Vol.234 (2), p.1630-1642 |
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| creator | Ma, Haiwen Li, Tao Tao, Zhennan Hai, Long Tong, Luqing Yi, Li Abeysekera, Iruni R. Liu, Peidong Xie, Yang Li, Jiabo Yuan, Feng Zhang, Chen Yang, Yihan Ming, Haolang Yu, Shengping Yang, Xuejun |
| description | Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.
There are some highlights in this paper: 1. An ion channel that is critical to tumor invasion is proposed. 2. This Ion cotransporters promoted epithelial‐mesenchymal transition process in glioma. 3. An intermediate mechanism for regulating epithelial–mesenchymal transition is proved. |
| doi_str_mv | 10.1002/jcp.27033 |
| format | Article |
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There are some highlights in this paper: 1. An ion channel that is critical to tumor invasion is proposed. 2. This Ion cotransporters promoted epithelial‐mesenchymal transition process in glioma. 3. An intermediate mechanism for regulating epithelial–mesenchymal transition is proved.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.27033</identifier><identifier>PMID: 30159893</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Brain cancer ; Brain Neoplasms - enzymology ; Brain Neoplasms - genetics ; Brain Neoplasms - pathology ; Brain tumors ; Cell Line, Tumor ; Cell Movement ; Cell size ; Chloride transport ; E-cadherin ; Epithelial-Mesenchymal Transition ; epithelial‐mesenchymal transition (EMT) ; Female ; Gene Expression Regulation, Neoplastic ; Glioblastoma ; Glioblastoma - enzymology ; Glioblastoma - genetics ; Glioblastoma - pathology ; Glioma ; Glioma cells ; Guanosine triphosphate ; Humans ; invasion and migration ; Invasiveness ; Malignancy ; Mesenchyme ; Mice, Nude ; Neoplasm Invasiveness ; Original ; Original s ; Pharmacology ; Polarity ; Rac1 and RhoA ; rac1 GTP-Binding Protein - genetics ; rac1 GTP-Binding Protein - metabolism ; Rac1 protein ; rhoA GTP-Binding Protein - genetics ; rhoA GTP-Binding Protein - metabolism ; RhoA protein ; Signal Transduction ; Signaling ; Sodium ; sodium‐potassium‐chloride cotransporter 1 (NKCC1) ; Solute Carrier Family 12, Member 2 - genetics ; Solute Carrier Family 12, Member 2 - metabolism ; Tumors ; Vimentin</subject><ispartof>Journal of cellular physiology, 2019-02, Vol.234 (2), p.1630-1642</ispartof><rights>2018 The Authors. Published by Wiley Periodicals, Inc.</rights><rights>2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.</rights><rights>2018. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4433-924b67a4de164f55f69385d93c200b29173b1672eef8340f659525dcc286e5903</citedby><cites>FETCH-LOGICAL-c4433-924b67a4de164f55f69385d93c200b29173b1672eef8340f659525dcc286e5903</cites><orcidid>0000-0002-3896-3174</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.27033$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.27033$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,781,785,886,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30159893$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Haiwen</creatorcontrib><creatorcontrib>Li, Tao</creatorcontrib><creatorcontrib>Tao, Zhennan</creatorcontrib><creatorcontrib>Hai, Long</creatorcontrib><creatorcontrib>Tong, Luqing</creatorcontrib><creatorcontrib>Yi, Li</creatorcontrib><creatorcontrib>Abeysekera, Iruni R.</creatorcontrib><creatorcontrib>Liu, Peidong</creatorcontrib><creatorcontrib>Xie, Yang</creatorcontrib><creatorcontrib>Li, Jiabo</creatorcontrib><creatorcontrib>Yuan, Feng</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Yang, Yihan</creatorcontrib><creatorcontrib>Ming, Haolang</creatorcontrib><creatorcontrib>Yu, Shengping</creatorcontrib><creatorcontrib>Yang, Xuejun</creatorcontrib><title>NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.
There are some highlights in this paper: 1. An ion channel that is critical to tumor invasion is proposed. 2. This Ion cotransporters promoted epithelial‐mesenchymal transition process in glioma. 3. An intermediate mechanism for regulating epithelial–mesenchymal transition is proved.</description><subject>Animals</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - enzymology</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain tumors</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell size</subject><subject>Chloride transport</subject><subject>E-cadherin</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>epithelial‐mesenchymal transition (EMT)</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma</subject><subject>Glioblastoma - enzymology</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - pathology</subject><subject>Glioma</subject><subject>Glioma cells</subject><subject>Guanosine triphosphate</subject><subject>Humans</subject><subject>invasion and migration</subject><subject>Invasiveness</subject><subject>Malignancy</subject><subject>Mesenchyme</subject><subject>Mice, Nude</subject><subject>Neoplasm Invasiveness</subject><subject>Original</subject><subject>Original s</subject><subject>Pharmacology</subject><subject>Polarity</subject><subject>Rac1 and RhoA</subject><subject>rac1 GTP-Binding Protein - genetics</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Rac1 protein</subject><subject>rhoA GTP-Binding Protein - genetics</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>RhoA protein</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Sodium</subject><subject>sodium‐potassium‐chloride cotransporter 1 (NKCC1)</subject><subject>Solute Carrier Family 12, Member 2 - genetics</subject><subject>Solute Carrier Family 12, Member 2 - metabolism</subject><subject>Tumors</subject><subject>Vimentin</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kEtOwzAQhi0EoqWw4ALIEisWaf2InXiDVKJSHi2gqqwt13FalzQJcR_qjiNwRk5CSguCBauRZj59M_MDcIpREyNEWlNdNEmAKN0DdYxE4PmckX1Qr2bYE8zHNXDk3BQhJASlh6BGEWYiFLQO-g_3UYRhUeazfG4c7PSHH2_vqX0xm542zkGbwe5VHy6tgoNJ3oYqi-FAaQydHWcqtdkYFmo-Wam1OwYHiUqdOdnVBni-7gyjG6_32L2N2j1P-z6lniD-iAfKjw3mfsJYwgUNWSyoJgiNiMABHWEeEGOSkPoo4UwwwmKtScgNE4g2wOXWWyxGMxNrk81LlcqitDNVrmWurPw7yexEjvOl5CQkIhCV4HwnKPPXhXFzOc0XZfWNkwRTxhEhJKioiy2ly9y50iQ_GzCSm-Rllbz8Sr5iz36f9EN-R10BrS2wsqlZ_2-Sd9HTVvkJlEmLqg</recordid><startdate>201902</startdate><enddate>201902</enddate><creator>Ma, Haiwen</creator><creator>Li, Tao</creator><creator>Tao, Zhennan</creator><creator>Hai, Long</creator><creator>Tong, Luqing</creator><creator>Yi, Li</creator><creator>Abeysekera, Iruni R.</creator><creator>Liu, Peidong</creator><creator>Xie, Yang</creator><creator>Li, Jiabo</creator><creator>Yuan, Feng</creator><creator>Zhang, Chen</creator><creator>Yang, Yihan</creator><creator>Ming, Haolang</creator><creator>Yu, Shengping</creator><creator>Yang, Xuejun</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><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>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3896-3174</orcidid></search><sort><creationdate>201902</creationdate><title>NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways</title><author>Ma, Haiwen ; Li, Tao ; Tao, Zhennan ; Hai, Long ; Tong, Luqing ; Yi, Li ; Abeysekera, Iruni R. ; Liu, Peidong ; Xie, Yang ; Li, Jiabo ; Yuan, Feng ; Zhang, Chen ; Yang, Yihan ; Ming, Haolang ; Yu, Shengping ; Yang, Xuejun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4433-924b67a4de164f55f69385d93c200b29173b1672eef8340f659525dcc286e5903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - enzymology</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain tumors</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell size</topic><topic>Chloride transport</topic><topic>E-cadherin</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>epithelial‐mesenchymal transition (EMT)</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glioblastoma</topic><topic>Glioblastoma - enzymology</topic><topic>Glioblastoma - genetics</topic><topic>Glioblastoma - pathology</topic><topic>Glioma</topic><topic>Glioma cells</topic><topic>Guanosine triphosphate</topic><topic>Humans</topic><topic>invasion and migration</topic><topic>Invasiveness</topic><topic>Malignancy</topic><topic>Mesenchyme</topic><topic>Mice, Nude</topic><topic>Neoplasm Invasiveness</topic><topic>Original</topic><topic>Original s</topic><topic>Pharmacology</topic><topic>Polarity</topic><topic>Rac1 and RhoA</topic><topic>rac1 GTP-Binding Protein - genetics</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Rac1 protein</topic><topic>rhoA GTP-Binding Protein - genetics</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>RhoA protein</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Sodium</topic><topic>sodium‐potassium‐chloride cotransporter 1 (NKCC1)</topic><topic>Solute Carrier Family 12, Member 2 - genetics</topic><topic>Solute Carrier Family 12, Member 2 - metabolism</topic><topic>Tumors</topic><topic>Vimentin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Haiwen</creatorcontrib><creatorcontrib>Li, Tao</creatorcontrib><creatorcontrib>Tao, Zhennan</creatorcontrib><creatorcontrib>Hai, Long</creatorcontrib><creatorcontrib>Tong, Luqing</creatorcontrib><creatorcontrib>Yi, Li</creatorcontrib><creatorcontrib>Abeysekera, Iruni R.</creatorcontrib><creatorcontrib>Liu, Peidong</creatorcontrib><creatorcontrib>Xie, Yang</creatorcontrib><creatorcontrib>Li, Jiabo</creatorcontrib><creatorcontrib>Yuan, Feng</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Yang, Yihan</creatorcontrib><creatorcontrib>Ming, Haolang</creatorcontrib><creatorcontrib>Yu, Shengping</creatorcontrib><creatorcontrib>Yang, Xuejun</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Haiwen</au><au>Li, Tao</au><au>Tao, Zhennan</au><au>Hai, Long</au><au>Tong, Luqing</au><au>Yi, Li</au><au>Abeysekera, Iruni R.</au><au>Liu, Peidong</au><au>Xie, Yang</au><au>Li, Jiabo</au><au>Yuan, Feng</au><au>Zhang, Chen</au><au>Yang, Yihan</au><au>Ming, Haolang</au><au>Yu, Shengping</au><au>Yang, Xuejun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J Cell Physiol</addtitle><date>2019-02</date><risdate>2019</risdate><volume>234</volume><issue>2</issue><spage>1630</spage><epage>1642</epage><pages>1630-1642</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><abstract>Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.
There are some highlights in this paper: 1. An ion channel that is critical to tumor invasion is proposed. 2. This Ion cotransporters promoted epithelial‐mesenchymal transition process in glioma. 3. An intermediate mechanism for regulating epithelial–mesenchymal transition is proved.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30159893</pmid><doi>10.1002/jcp.27033</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-3896-3174</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of cellular physiology, 2019-02, Vol.234 (2), p.1630-1642 |
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| subjects | Animals Brain cancer Brain Neoplasms - enzymology Brain Neoplasms - genetics Brain Neoplasms - pathology Brain tumors Cell Line, Tumor Cell Movement Cell size Chloride transport E-cadherin Epithelial-Mesenchymal Transition epithelial‐mesenchymal transition (EMT) Female Gene Expression Regulation, Neoplastic Glioblastoma Glioblastoma - enzymology Glioblastoma - genetics Glioblastoma - pathology Glioma Glioma cells Guanosine triphosphate Humans invasion and migration Invasiveness Malignancy Mesenchyme Mice, Nude Neoplasm Invasiveness Original Original s Pharmacology Polarity Rac1 and RhoA rac1 GTP-Binding Protein - genetics rac1 GTP-Binding Protein - metabolism Rac1 protein rhoA GTP-Binding Protein - genetics rhoA GTP-Binding Protein - metabolism RhoA protein Signal Transduction Signaling Sodium sodium‐potassium‐chloride cotransporter 1 (NKCC1) Solute Carrier Family 12, Member 2 - genetics Solute Carrier Family 12, Member 2 - metabolism Tumors Vimentin |
| title | NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways |
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