Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermeth...
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| Veröffentlicht in: | Oncotarget 2015-08, Vol.6 (22), p.18905-18920 |
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| creator | Wang, Jinghan Zhang, Keqiang Wang, Jinhui Wu, Xiwei Liu, Xiyong Li, Bin Zhu, Yan Yu, Yong Cheng, Qingbao Hu, Zhenli Guo, Chao Hu, Shuya Mu, Bing Tsai, Chun-Hao Li, Jie Smith, Lynne Yang, Lu Liu, Qi Chu, Peiguo Chang, Vincent Zhang, Baihe Wu, Mengchao Jiang, Xiaoqing Yen, Yun |
| description | Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression. |
| doi_str_mv | 10.18632/oncotarget.4305 |
| format | Article |
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In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.4305</identifier><identifier>PMID: 26056085</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Base Sequence ; beta Catenin - metabolism ; Bile Duct Neoplasms - enzymology ; Bile Duct Neoplasms - genetics ; Bile Duct Neoplasms - metabolism ; Bile Duct Neoplasms - pathology ; Cell Growth Processes - physiology ; Cell Line, Tumor ; Cell Movement - physiology ; Cholangiocarcinoma - enzymology ; Cholangiocarcinoma - genetics ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; DNA Methylation ; Down-Regulation ; Female ; Gene Knockdown Techniques ; Genes, Tumor Suppressor ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Protein-Serine-Threonine Kinases - biosynthesis ; Protein-Serine-Threonine Kinases - metabolism ; Research Paper ; Wnt Signaling Pathway</subject><ispartof>Oncotarget, 2015-08, Vol.6 (22), p.18905-18920</ispartof><rights>Copyright: © 2015 Wang et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-2181f9fba5109cdfeb05772b32bb166d93bebeecebfc42785afdda6f082e3f513</citedby><cites>FETCH-LOGICAL-c396t-2181f9fba5109cdfeb05772b32bb166d93bebeecebfc42785afdda6f082e3f513</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/PMC4662463/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662463/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26056085$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Jinghan</creatorcontrib><creatorcontrib>Zhang, Keqiang</creatorcontrib><creatorcontrib>Wang, Jinhui</creatorcontrib><creatorcontrib>Wu, Xiwei</creatorcontrib><creatorcontrib>Liu, Xiyong</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Zhu, Yan</creatorcontrib><creatorcontrib>Yu, Yong</creatorcontrib><creatorcontrib>Cheng, Qingbao</creatorcontrib><creatorcontrib>Hu, Zhenli</creatorcontrib><creatorcontrib>Guo, Chao</creatorcontrib><creatorcontrib>Hu, Shuya</creatorcontrib><creatorcontrib>Mu, Bing</creatorcontrib><creatorcontrib>Tsai, Chun-Hao</creatorcontrib><creatorcontrib>Li, Jie</creatorcontrib><creatorcontrib>Smith, Lynne</creatorcontrib><creatorcontrib>Yang, Lu</creatorcontrib><creatorcontrib>Liu, Qi</creatorcontrib><creatorcontrib>Chu, Peiguo</creatorcontrib><creatorcontrib>Chang, Vincent</creatorcontrib><creatorcontrib>Zhang, Baihe</creatorcontrib><creatorcontrib>Wu, Mengchao</creatorcontrib><creatorcontrib>Jiang, Xiaoqing</creatorcontrib><creatorcontrib>Yen, Yun</creatorcontrib><title>Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression.</description><subject>Base Sequence</subject><subject>beta Catenin - metabolism</subject><subject>Bile Duct Neoplasms - enzymology</subject><subject>Bile Duct Neoplasms - genetics</subject><subject>Bile Duct Neoplasms - metabolism</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Cell Growth Processes - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - physiology</subject><subject>Cholangiocarcinoma - enzymology</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>DNA Methylation</subject><subject>Down-Regulation</subject><subject>Female</subject><subject>Gene Knockdown Techniques</subject><subject>Genes, Tumor Suppressor</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Protein-Serine-Threonine Kinases - biosynthesis</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Research Paper</subject><subject>Wnt Signaling Pathway</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>eNpVUctu1TAQjRCIVm33rJCXbG7xI3aSDRJU5SGu1A0VS2vijBOjxA62A-VT-Ft821KKN3Pmdc5Yp6peMHrOWiX46-BNyBBHzOe1oPJJdcy6uttxKcXTR_ioOkvpGy1P1k3Lu-fVEVdUKtrK4-r3tR8w4s0aMSUXPAmW7D-_YyRvS4gkbettp0CXCBRgHGQcyE-XJ4J-Am9K9tVnktzoYXZ-JOAHshRY8lI3E0QwGaNL2Zl0EJi2BTxxPkeYcIVSLlNhBj-6YCAa58MCp9UzC3PCs_t4Ul2_v_xy8XG3v_rw6eLtfmdEp_KOs5bZzvYgGe3MYLGnsml4L3jfM6WGTvTYIxrsral500qwwwDK0pajsJKJk-rNHe-69QsOBg9nzXqNboH4Swdw-v-Od5Meww9dK8VrJQrBq3uCGL5vmLJeXDI4l_9g2JJmDVWyCCtaRundqIkhpYj2QYZRfWuq_meqPphaVl4-Pu9h4a-F4g-mxKdW</recordid><startdate>20150807</startdate><enddate>20150807</enddate><creator>Wang, Jinghan</creator><creator>Zhang, Keqiang</creator><creator>Wang, Jinhui</creator><creator>Wu, Xiwei</creator><creator>Liu, Xiyong</creator><creator>Li, Bin</creator><creator>Zhu, Yan</creator><creator>Yu, Yong</creator><creator>Cheng, Qingbao</creator><creator>Hu, Zhenli</creator><creator>Guo, Chao</creator><creator>Hu, Shuya</creator><creator>Mu, Bing</creator><creator>Tsai, Chun-Hao</creator><creator>Li, Jie</creator><creator>Smith, Lynne</creator><creator>Yang, Lu</creator><creator>Liu, Qi</creator><creator>Chu, Peiguo</creator><creator>Chang, Vincent</creator><creator>Zhang, Baihe</creator><creator>Wu, Mengchao</creator><creator>Jiang, Xiaoqing</creator><creator>Yen, Yun</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>Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma</title><author>Wang, Jinghan ; Zhang, Keqiang ; Wang, Jinhui ; Wu, Xiwei ; Liu, Xiyong ; Li, Bin ; Zhu, Yan ; Yu, Yong ; Cheng, Qingbao ; Hu, Zhenli ; Guo, Chao ; Hu, Shuya ; Mu, Bing ; Tsai, Chun-Hao ; Li, Jie ; Smith, Lynne ; Yang, Lu ; Liu, Qi ; Chu, Peiguo ; Chang, Vincent ; Zhang, Baihe ; Wu, Mengchao ; Jiang, Xiaoqing ; Yen, Yun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-2181f9fba5109cdfeb05772b32bb166d93bebeecebfc42785afdda6f082e3f513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Base Sequence</topic><topic>beta Catenin - metabolism</topic><topic>Bile Duct Neoplasms - enzymology</topic><topic>Bile Duct Neoplasms - genetics</topic><topic>Bile Duct Neoplasms - metabolism</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Cell Growth Processes - physiology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - physiology</topic><topic>Cholangiocarcinoma - enzymology</topic><topic>Cholangiocarcinoma - genetics</topic><topic>Cholangiocarcinoma - metabolism</topic><topic>Cholangiocarcinoma - pathology</topic><topic>DNA Methylation</topic><topic>Down-Regulation</topic><topic>Female</topic><topic>Gene Knockdown Techniques</topic><topic>Genes, Tumor Suppressor</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Protein-Serine-Threonine Kinases - biosynthesis</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Research Paper</topic><topic>Wnt Signaling Pathway</topic><toplevel>online_resources</toplevel><creatorcontrib>Wang, Jinghan</creatorcontrib><creatorcontrib>Zhang, Keqiang</creatorcontrib><creatorcontrib>Wang, Jinhui</creatorcontrib><creatorcontrib>Wu, Xiwei</creatorcontrib><creatorcontrib>Liu, Xiyong</creatorcontrib><creatorcontrib>Li, Bin</creatorcontrib><creatorcontrib>Zhu, Yan</creatorcontrib><creatorcontrib>Yu, Yong</creatorcontrib><creatorcontrib>Cheng, Qingbao</creatorcontrib><creatorcontrib>Hu, Zhenli</creatorcontrib><creatorcontrib>Guo, Chao</creatorcontrib><creatorcontrib>Hu, Shuya</creatorcontrib><creatorcontrib>Mu, Bing</creatorcontrib><creatorcontrib>Tsai, Chun-Hao</creatorcontrib><creatorcontrib>Li, Jie</creatorcontrib><creatorcontrib>Smith, Lynne</creatorcontrib><creatorcontrib>Yang, Lu</creatorcontrib><creatorcontrib>Liu, Qi</creatorcontrib><creatorcontrib>Chu, Peiguo</creatorcontrib><creatorcontrib>Chang, Vincent</creatorcontrib><creatorcontrib>Zhang, Baihe</creatorcontrib><creatorcontrib>Wu, Mengchao</creatorcontrib><creatorcontrib>Jiang, Xiaoqing</creatorcontrib><creatorcontrib>Yen, Yun</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, Jinghan</au><au>Zhang, Keqiang</au><au>Wang, Jinhui</au><au>Wu, Xiwei</au><au>Liu, Xiyong</au><au>Li, Bin</au><au>Zhu, Yan</au><au>Yu, Yong</au><au>Cheng, Qingbao</au><au>Hu, Zhenli</au><au>Guo, Chao</au><au>Hu, Shuya</au><au>Mu, Bing</au><au>Tsai, Chun-Hao</au><au>Li, Jie</au><au>Smith, Lynne</au><au>Yang, Lu</au><au>Liu, Qi</au><au>Chu, Peiguo</au><au>Chang, Vincent</au><au>Zhang, Baihe</au><au>Wu, Mengchao</au><au>Jiang, Xiaoqing</au><au>Yen, Yun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-08-07</date><risdate>2015</risdate><volume>6</volume><issue>22</issue><spage>18905</spage><epage>18920</epage><pages>18905-18920</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26056085</pmid><doi>10.18632/oncotarget.4305</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free E- Journals; PubMed Central Open Access |
| subjects | Base Sequence beta Catenin - metabolism Bile Duct Neoplasms - enzymology Bile Duct Neoplasms - genetics Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Cell Growth Processes - physiology Cell Line, Tumor Cell Movement - physiology Cholangiocarcinoma - enzymology Cholangiocarcinoma - genetics Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology DNA Methylation Down-Regulation Female Gene Knockdown Techniques Genes, Tumor Suppressor Humans Male Middle Aged Molecular Sequence Data Protein-Serine-Threonine Kinases - biosynthesis Protein-Serine-Threonine Kinases - metabolism Research Paper Wnt Signaling Pathway |
| title | Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma |
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