Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions
Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene s...
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| Veröffentlicht in: | Oncotarget 2015-08, Vol.6 (22), p.19264-19278 |
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| creator | Wang, Juan Liu, Guomu Li, Qiongshu Wang, Fang Xie, Fei Zhai, Ruiping Guo, Yingying Chen, Tanxiu Zhang, Nannan Ni, Weihua Yuan, Hongyan Tai, Guixiang |
| description | Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-β)1, TGF-β type I receptor (TβRI) inhibitor, TGF-β1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-β via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TβRI inhibitor or TGF-β1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-β/TβRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy. |
| doi_str_mv | 10.18632/oncotarget.4267 |
| format | Article |
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In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-β)1, TGF-β type I receptor (TβRI) inhibitor, TGF-β1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-β via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TβRI inhibitor or TGF-β1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-β/TβRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.4267</identifier><identifier>PMID: 26057631</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell Movement - physiology ; Hep G2 Cells ; Humans ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; MAP Kinase Signaling System ; Mucin-1 - genetics ; Mucin-1 - metabolism ; Phosphorylation ; Research Paper ; Smad2 Protein - genetics ; Smad2 Protein - metabolism ; Transfection</subject><ispartof>Oncotarget, 2015-08, Vol.6 (22), p.19264-19278</ispartof><rights>Copyright: © 2015 Wang et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-bc3d7cd78782dd102b3300d8b91f3dc7e92cd00487f359dd9edd887be38994c93</citedby><cites>FETCH-LOGICAL-c462t-bc3d7cd78782dd102b3300d8b91f3dc7e92cd00487f359dd9edd887be38994c93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662489/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662489/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26057631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Juan</creatorcontrib><creatorcontrib>Liu, Guomu</creatorcontrib><creatorcontrib>Li, Qiongshu</creatorcontrib><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Xie, Fei</creatorcontrib><creatorcontrib>Zhai, Ruiping</creatorcontrib><creatorcontrib>Guo, Yingying</creatorcontrib><creatorcontrib>Chen, Tanxiu</creatorcontrib><creatorcontrib>Zhang, Nannan</creatorcontrib><creatorcontrib>Ni, Weihua</creatorcontrib><creatorcontrib>Yuan, Hongyan</creatorcontrib><creatorcontrib>Tai, Guixiang</creatorcontrib><title>Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-β)1, TGF-β type I receptor (TβRI) inhibitor, TGF-β1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-β via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TβRI inhibitor or TGF-β1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-β/TβRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy.</description><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - physiology</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>MAP Kinase Signaling System</subject><subject>Mucin-1 - genetics</subject><subject>Mucin-1 - metabolism</subject><subject>Phosphorylation</subject><subject>Research Paper</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Transfection</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1vFCEYnhiNbWrvngxHL1P5mBngYmI2atVWD-qZMPDOLjoDIzCb9Lf4Z8vs1raSEF7g-XjhqaqXBF8Q0TH6JngTso5byBcN7fiT6pTIRta0bdnTR_VJdZ7SL1xG23BB5fPqhHa45R0jp9Xf68U4T9AcwxQyJJR3gCa3jTq74JH2Fjm_12ndhAHtYNY5GBjHZdQRGR0LO0warUcJ7Z1Gn79-qSewTmewaN6FVGa8GY96ReL7pC1FOh-cNnWGODmvx4PV6PxviCjCtoDTi-rZoMcE53frWfXzw_sfm8v66tvHT5t3V7VpOprr3jDLjeWiPM5agmnPGMZW9JIMzBoOkhqLcSP4wFpprQRrheA9MCFlYyQ7q94edeelL50b8DnqUc3RTTreqKCd-v_Gu53ahr1quo42YhV4fScQw58FUlaTS-uPaA9hSYpw3LVcEEkKFB-hJoaUIgz3NgSrQ6zqIVa1xloorx63d0_4FyK7BSlnpXw</recordid><startdate>20150807</startdate><enddate>20150807</enddate><creator>Wang, Juan</creator><creator>Liu, Guomu</creator><creator>Li, Qiongshu</creator><creator>Wang, Fang</creator><creator>Xie, Fei</creator><creator>Zhai, Ruiping</creator><creator>Guo, Yingying</creator><creator>Chen, Tanxiu</creator><creator>Zhang, Nannan</creator><creator>Ni, Weihua</creator><creator>Yuan, Hongyan</creator><creator>Tai, Guixiang</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150807</creationdate><title>Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions</title><author>Wang, Juan ; Liu, Guomu ; Li, Qiongshu ; Wang, Fang ; Xie, Fei ; Zhai, Ruiping ; Guo, Yingying ; Chen, Tanxiu ; Zhang, Nannan ; Ni, Weihua ; Yuan, Hongyan ; Tai, Guixiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-bc3d7cd78782dd102b3300d8b91f3dc7e92cd00487f359dd9edd887be38994c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - physiology</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>MAP Kinase Signaling System</topic><topic>Mucin-1 - genetics</topic><topic>Mucin-1 - metabolism</topic><topic>Phosphorylation</topic><topic>Research Paper</topic><topic>Smad2 Protein - genetics</topic><topic>Smad2 Protein - metabolism</topic><topic>Transfection</topic><toplevel>online_resources</toplevel><creatorcontrib>Wang, Juan</creatorcontrib><creatorcontrib>Liu, Guomu</creatorcontrib><creatorcontrib>Li, Qiongshu</creatorcontrib><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Xie, Fei</creatorcontrib><creatorcontrib>Zhai, Ruiping</creatorcontrib><creatorcontrib>Guo, Yingying</creatorcontrib><creatorcontrib>Chen, Tanxiu</creatorcontrib><creatorcontrib>Zhang, Nannan</creatorcontrib><creatorcontrib>Ni, Weihua</creatorcontrib><creatorcontrib>Yuan, Hongyan</creatorcontrib><creatorcontrib>Tai, Guixiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Juan</au><au>Liu, Guomu</au><au>Li, Qiongshu</au><au>Wang, Fang</au><au>Xie, Fei</au><au>Zhai, Ruiping</au><au>Guo, Yingying</au><au>Chen, Tanxiu</au><au>Zhang, Nannan</au><au>Ni, Weihua</au><au>Yuan, Hongyan</au><au>Tai, Guixiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-08-07</date><risdate>2015</risdate><volume>6</volume><issue>22</issue><spage>19264</spage><epage>19278</epage><pages>19264-19278</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-β)1, TGF-β type I receptor (TβRI) inhibitor, TGF-β1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-β via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TβRI inhibitor or TGF-β1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-β/TβRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26057631</pmid><doi>10.18632/oncotarget.4267</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell Movement - physiology Hep G2 Cells Humans Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology MAP Kinase Signaling System Mucin-1 - genetics Mucin-1 - metabolism Phosphorylation Research Paper Smad2 Protein - genetics Smad2 Protein - metabolism Transfection |
| title | Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions |
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