PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma
Deregulation of serine/threonine kinase contributes to the development and progression of human diseases. PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK...
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| Veröffentlicht in: | Oncotarget 2017-07, Vol.8 (29), p.47195-47205 |
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| creator | Yang, Yu-Feng Pan, Ying-Hua Cao, Yun Fu, Jia Yang, Xia Zhang, Mei-Fang Tian, Qiu-Hong |
| description | Deregulation of serine/threonine kinase contributes to the development and progression of human diseases. PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK expression is increased and associated with larger tumor size, presence of vascular invasion, lymph node metastasis and poor overall and disease-free survivals in two independent cohorts of 879 patients with HCC. In vitro and in vivo data demonstrate PBK exerts oncogenic functions in HCC via activation of β-Catenin signaling pathway. The inhibition of β-Catenin by siRNAs or XAV-939 significantly attenuates PBK-mediated malignant phenotypes. PBK is further identified as a downstream effector of FoxM1. In clinical samples, PBK expression is positively correlated with the expression of FoxM1 and nuclear β-Catenin. Collectively, these findings suggest PBK functions as an oncogene in HCC and the newly identified FoxM1/PBK/β-Catenin axis serves as a promising prognostic factor as well as therapeutic intervention for HCC. |
| doi_str_mv | 10.18632/oncotarget.17587 |
| format | Article |
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PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK expression is increased and associated with larger tumor size, presence of vascular invasion, lymph node metastasis and poor overall and disease-free survivals in two independent cohorts of 879 patients with HCC. In vitro and in vivo data demonstrate PBK exerts oncogenic functions in HCC via activation of β-Catenin signaling pathway. The inhibition of β-Catenin by siRNAs or XAV-939 significantly attenuates PBK-mediated malignant phenotypes. PBK is further identified as a downstream effector of FoxM1. In clinical samples, PBK expression is positively correlated with the expression of FoxM1 and nuclear β-Catenin. Collectively, these findings suggest PBK functions as an oncogene in HCC and the newly identified FoxM1/PBK/β-Catenin axis serves as a promising prognostic factor as well as therapeutic intervention for HCC.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.17587</identifier><identifier>PMID: 28525379</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Adult ; Aged ; Animals ; beta Catenin - metabolism ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - mortality ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Forkhead Box Protein M1 - metabolism ; Gene Expression Regulation, Neoplastic ; Heterografts ; Humans ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - mortality ; Liver Neoplasms - pathology ; Male ; Mice ; Middle Aged ; Mitogen-Activated Protein Kinase Kinases - genetics ; Mitogen-Activated Protein Kinase Kinases - metabolism ; Neoplasm Grading ; Neoplasm Staging ; Oncogenes ; Phenotype ; Research Paper ; Signal Transduction ; Transcription, Genetic ; Tumor Burden</subject><ispartof>Oncotarget, 2017-07, Vol.8 (29), p.47195-47205</ispartof><rights>Copyright: © 2017 Yang et al. 2017</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-77e6cbc81420272f54b4d8c512871510217deef0adda67983ac54dc265a020613</citedby><cites>FETCH-LOGICAL-c356t-77e6cbc81420272f54b4d8c512871510217deef0adda67983ac54dc265a020613</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/PMC5564556/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564556/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28525379$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Yu-Feng</creatorcontrib><creatorcontrib>Pan, Ying-Hua</creatorcontrib><creatorcontrib>Cao, Yun</creatorcontrib><creatorcontrib>Fu, Jia</creatorcontrib><creatorcontrib>Yang, Xia</creatorcontrib><creatorcontrib>Zhang, Mei-Fang</creatorcontrib><creatorcontrib>Tian, Qiu-Hong</creatorcontrib><title>PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Deregulation of serine/threonine kinase contributes to the development and progression of human diseases. PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK expression is increased and associated with larger tumor size, presence of vascular invasion, lymph node metastasis and poor overall and disease-free survivals in two independent cohorts of 879 patients with HCC. In vitro and in vivo data demonstrate PBK exerts oncogenic functions in HCC via activation of β-Catenin signaling pathway. The inhibition of β-Catenin by siRNAs or XAV-939 significantly attenuates PBK-mediated malignant phenotypes. PBK is further identified as a downstream effector of FoxM1. In clinical samples, PBK expression is positively correlated with the expression of FoxM1 and nuclear β-Catenin. Collectively, these findings suggest PBK functions as an oncogene in HCC and the newly identified FoxM1/PBK/β-Catenin axis serves as a promising prognostic factor as well as therapeutic intervention for HCC.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - mortality</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Forkhead Box Protein M1 - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - mortality</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Mitogen-Activated Protein Kinase Kinases - genetics</subject><subject>Mitogen-Activated Protein Kinase Kinases - metabolism</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Staging</subject><subject>Oncogenes</subject><subject>Phenotype</subject><subject>Research Paper</subject><subject>Signal Transduction</subject><subject>Transcription, Genetic</subject><subject>Tumor Burden</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFu1DAQhiMEolXpA3BBPnJoWtuxY-eChLYUKhWVA1y4WBNnkjUkdrC9K_YJeB8ehGci25bSjjQaj_zPN7b-onjJ6CnTdcXPgrchQxwwnzIltXpSHLJGNCWXsnr64HxQHKf0jS4hhdK8eV4ccC25rFRzWPz6dP6VtM53zg_ku_OQ8IREHDYjZOxIuyMX4edHdkLQr8FbTGSC0Q0efCbzGn3IuxnJ1gEBm90WsguehJ78-V2uFoJ3nqS9fNzzl2aNM-RgcRyXDZFYiNb5MMGL4lkPY8Lju3pUfLl493n1oby6fn-5entV2krWuVQKa9tazQSnXPFeilZ02krGtWKSUc5Uh9hT6DqoVaMrsFJ0ltcSKKc1q46KN7fcedNO2Fn0OcJo5ugmiDsTwJnHN96tzRC2RspaLLkAXt8BYvixwZTN5NL-P-AxbJJhDaW6ErQWi5TdSm0MKUXs79cwam48NP89NDceLjOvHr7vfuKfY9Vfqv-eJg</recordid><startdate>20170718</startdate><enddate>20170718</enddate><creator>Yang, Yu-Feng</creator><creator>Pan, Ying-Hua</creator><creator>Cao, Yun</creator><creator>Fu, Jia</creator><creator>Yang, Xia</creator><creator>Zhang, Mei-Fang</creator><creator>Tian, Qiu-Hong</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>20170718</creationdate><title>PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma</title><author>Yang, Yu-Feng ; Pan, Ying-Hua ; Cao, Yun ; Fu, Jia ; Yang, Xia ; Zhang, Mei-Fang ; Tian, Qiu-Hong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-77e6cbc81420272f54b4d8c512871510217deef0adda67983ac54dc265a020613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>beta Catenin - metabolism</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - mortality</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Forkhead Box Protein M1 - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - mortality</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Mitogen-Activated Protein Kinase Kinases - genetics</topic><topic>Mitogen-Activated Protein Kinase Kinases - metabolism</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Staging</topic><topic>Oncogenes</topic><topic>Phenotype</topic><topic>Research Paper</topic><topic>Signal Transduction</topic><topic>Transcription, Genetic</topic><topic>Tumor Burden</topic><toplevel>online_resources</toplevel><creatorcontrib>Yang, Yu-Feng</creatorcontrib><creatorcontrib>Pan, Ying-Hua</creatorcontrib><creatorcontrib>Cao, Yun</creatorcontrib><creatorcontrib>Fu, Jia</creatorcontrib><creatorcontrib>Yang, Xia</creatorcontrib><creatorcontrib>Zhang, Mei-Fang</creatorcontrib><creatorcontrib>Tian, Qiu-Hong</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>Yang, Yu-Feng</au><au>Pan, Ying-Hua</au><au>Cao, Yun</au><au>Fu, Jia</au><au>Yang, Xia</au><au>Zhang, Mei-Fang</au><au>Tian, Qiu-Hong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2017-07-18</date><risdate>2017</risdate><volume>8</volume><issue>29</issue><spage>47195</spage><epage>47205</epage><pages>47195-47205</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Deregulation of serine/threonine kinase contributes to the development and progression of human diseases. PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK expression is increased and associated with larger tumor size, presence of vascular invasion, lymph node metastasis and poor overall and disease-free survivals in two independent cohorts of 879 patients with HCC. In vitro and in vivo data demonstrate PBK exerts oncogenic functions in HCC via activation of β-Catenin signaling pathway. The inhibition of β-Catenin by siRNAs or XAV-939 significantly attenuates PBK-mediated malignant phenotypes. PBK is further identified as a downstream effector of FoxM1. In clinical samples, PBK expression is positively correlated with the expression of FoxM1 and nuclear β-Catenin. 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| subjects | Adult Aged Animals beta Catenin - metabolism Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - mortality Carcinoma, Hepatocellular - pathology Cell Line, Tumor Disease Models, Animal Female Forkhead Box Protein M1 - metabolism Gene Expression Regulation, Neoplastic Heterografts Humans Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - mortality Liver Neoplasms - pathology Male Mice Middle Aged Mitogen-Activated Protein Kinase Kinases - genetics Mitogen-Activated Protein Kinase Kinases - metabolism Neoplasm Grading Neoplasm Staging Oncogenes Phenotype Research Paper Signal Transduction Transcription, Genetic Tumor Burden |
| title | PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma |
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