BMP4 Administration Induces Differentiation of CD133+ Hepatic Cancer Stem Cells, Blocking Their Contributions to Hepatocellular Carcinoma
CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2012-08, Vol.72 (16), p.4276-4285 |
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| creator | Zhang, Lixing Sun, Hefen Zhao, Fangyu Lu, Ping Ge, Chao Li, Hong Hou, Helei Yan, Mingxia Chen, Taoyang Jiang, Guoping Xie, Haiyang Cui, Ying Huang, Xiaowu Fan, Jia Yao, Ming Li, Jinjun |
| description | CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs. |
| doi_str_mv | 10.1158/0008-5472.CAN-12-1013 |
| format | Article |
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Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-12-1013</identifier><identifier>PMID: 22773665</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>AC133 Antigen ; Antigens, CD - biosynthesis ; Antineoplastic agents ; Biological and medical sciences ; Bone Morphogenetic Protein 4 - genetics ; Bone Morphogenetic Protein 4 - metabolism ; Bone Morphogenetic Protein 4 - pharmacology ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Differentiation - drug effects ; Gastroenterology. Liver. Pancreas. Abdomen ; Glycoproteins - biosynthesis ; Humans ; Liver Neoplasms - drug therapy ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Medical sciences ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - pathology ; Peptides ; Pharmacology. Drug treatments ; Phosphorylation ; Smad6 Protein - biosynthesis ; Smad6 Protein - genetics ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2012-08, Vol.72 (16), p.4276-4285</ispartof><rights>2015 INIST-CNRS</rights><rights>2012 AACR.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-8655de57f9f84ab93f6cb331e125335a2ed55c5b7832d0e5042742298ad2ca213</citedby><cites>FETCH-LOGICAL-c424t-8655de57f9f84ab93f6cb331e125335a2ed55c5b7832d0e5042742298ad2ca213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3357,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26285890$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22773665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Lixing</creatorcontrib><creatorcontrib>Sun, Hefen</creatorcontrib><creatorcontrib>Zhao, Fangyu</creatorcontrib><creatorcontrib>Lu, Ping</creatorcontrib><creatorcontrib>Ge, Chao</creatorcontrib><creatorcontrib>Li, Hong</creatorcontrib><creatorcontrib>Hou, Helei</creatorcontrib><creatorcontrib>Yan, Mingxia</creatorcontrib><creatorcontrib>Chen, Taoyang</creatorcontrib><creatorcontrib>Jiang, Guoping</creatorcontrib><creatorcontrib>Xie, Haiyang</creatorcontrib><creatorcontrib>Cui, Ying</creatorcontrib><creatorcontrib>Huang, Xiaowu</creatorcontrib><creatorcontrib>Fan, Jia</creatorcontrib><creatorcontrib>Yao, Ming</creatorcontrib><creatorcontrib>Li, Jinjun</creatorcontrib><title>BMP4 Administration Induces Differentiation of CD133+ Hepatic Cancer Stem Cells, Blocking Their Contributions to Hepatocellular Carcinoma</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.</description><subject>AC133 Antigen</subject><subject>Antigens, CD - biosynthesis</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Bone Morphogenetic Protein 4 - genetics</subject><subject>Bone Morphogenetic Protein 4 - metabolism</subject><subject>Bone Morphogenetic Protein 4 - pharmacology</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Differentiation - drug effects</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Glycoproteins - biosynthesis</subject><subject>Humans</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Peptides</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Smad6 Protein - biosynthesis</subject><subject>Smad6 Protein - genetics</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQhy0EotvCI4B8QUKCFP-bxDlu09JWagGJcrYcxwZDYi92cuAReGsc7bYce7I8_n4zI38IvaLklFKQHwghsgLRsNNu-6mirKKE8idoQ4HLqhECnqLNA3OEjnP-Wa5ACTxHR4w1Da9r2KC_Z7dfBN4Okw8-z0nPPgZ8HYbF2IzPvXM22TD7fT063J1Tzt_hK7srJYM7HYxN-OtsJ9zZcczv8dkYzS8fvuO7H9Yn3MUwJ98va4OM57iPRlPgZdTlXSfjQ5z0C_TM6THbl4fzBH37eHHXXVU3ny-vu-1NZQQTcyVrgMFC41onhe5b7mrTc04tZcA5aGYHAAN9IzkbiAUiWCMYa6UemNGM8hP0dt93l-LvxeZZTT6v6-hg45IVrWvJ6oZJeBwlXNC24XTtCnvUpJhzsk7tkp90-lMgtQpTqwy1ylBFmKJMrcJK7vVhxNJPdnhI3RsqwJsDoLPRo0vlx33-z9VlUdkS_g9qXJ09</recordid><startdate>20120815</startdate><enddate>20120815</enddate><creator>Zhang, Lixing</creator><creator>Sun, Hefen</creator><creator>Zhao, Fangyu</creator><creator>Lu, Ping</creator><creator>Ge, Chao</creator><creator>Li, Hong</creator><creator>Hou, Helei</creator><creator>Yan, Mingxia</creator><creator>Chen, Taoyang</creator><creator>Jiang, Guoping</creator><creator>Xie, Haiyang</creator><creator>Cui, Ying</creator><creator>Huang, Xiaowu</creator><creator>Fan, Jia</creator><creator>Yao, Ming</creator><creator>Li, Jinjun</creator><general>American Association for Cancer Research</general><scope>IQODW</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120815</creationdate><title>BMP4 Administration Induces Differentiation of CD133+ Hepatic Cancer Stem Cells, Blocking Their Contributions to Hepatocellular Carcinoma</title><author>Zhang, Lixing ; Sun, Hefen ; Zhao, Fangyu ; Lu, Ping ; Ge, Chao ; Li, Hong ; Hou, Helei ; Yan, Mingxia ; Chen, Taoyang ; Jiang, Guoping ; Xie, Haiyang ; Cui, Ying ; Huang, Xiaowu ; Fan, Jia ; Yao, Ming ; Li, Jinjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-8655de57f9f84ab93f6cb331e125335a2ed55c5b7832d0e5042742298ad2ca213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>AC133 Antigen</topic><topic>Antigens, CD - biosynthesis</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Bone Morphogenetic Protein 4 - genetics</topic><topic>Bone Morphogenetic Protein 4 - metabolism</topic><topic>Bone Morphogenetic Protein 4 - pharmacology</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Differentiation - drug effects</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Glycoproteins - biosynthesis</topic><topic>Humans</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Peptides</topic><topic>Pharmacology. 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Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>22773665</pmid><doi>10.1158/0008-5472.CAN-12-1013</doi><tpages>10</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2012-08, Vol.72 (16), p.4276-4285 |
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| subjects | AC133 Antigen Antigens, CD - biosynthesis Antineoplastic agents Biological and medical sciences Bone Morphogenetic Protein 4 - genetics Bone Morphogenetic Protein 4 - metabolism Bone Morphogenetic Protein 4 - pharmacology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Differentiation - drug effects Gastroenterology. Liver. Pancreas. Abdomen Glycoproteins - biosynthesis Humans Liver Neoplasms - drug therapy Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical sciences Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - pathology Peptides Pharmacology. Drug treatments Phosphorylation Smad6 Protein - biosynthesis Smad6 Protein - genetics Tumors |
| title | BMP4 Administration Induces Differentiation of CD133+ Hepatic Cancer Stem Cells, Blocking Their Contributions to Hepatocellular Carcinoma |
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