Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma
Background Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homolo...
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| Veröffentlicht in: | Hepatology international 2020-05, Vol.14 (3), p.373-384 |
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| description | Background
Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.
Methods
Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.
Results
Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of
BCL9
and
BCL9L
was upregulated in human HCC and increased with progressing dedifferentiation. For
BCL9L
, higher expression was observed in tumors of larger size. Overexpression of
BCL9
and
BCL9L
correlated with poor overall survival, especially in HCC without activated Wnt signaling.
Conclusion
Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
Graphic abstract |
| doi_str_mv | 10.1007/s12072-019-09977-w |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7220899</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2336990696</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-51cfdab3bf6023dcb7dbab532f339e0b49b6acf001af4aa9c321cedef5fe89fb3</originalsourceid><addsrcrecordid>eNp9UcFu1DAQtRCIlsIP9FBF4sIlMLaTuL5UKitokVZCSK04WmNnvE2Vtbd2QsXf4-2WLXDgNKOZ997M02PsmMN7DqA-ZC5AiRq4rkFrper7Z-yQa9nV0Db8-b6X8oC9yvkWoG073r1kB5I3TaGIQ_bte5iqPOE057qnDYWeyiAGF1cUBlelOFIVffVxsdQVhv6hWVZDqG5og1N0NI7ziKlymNwQ4hpfsxcex0xvHusRu_786WpxWS-_XnxZnC9r16hmqlvufI9WWt-BkL2zqrdoWym8lJrANtp26DwAR98gaicFd9STbz2dam_lETvb6W5mu6belb8TjmaThjWmnybiYP7ehOHGrOIPo4SAU62LwLtHgRTvZsqTWQ956wcDxTkbIWWnNXS6K9C3_0Bv45xCsWdEA6KFVqmtoNihXIo5J_L7ZziYbWJml5gpiZmHxMx9IZ38aWNP-R1RAcgdIJdVWFF6uv0f2V9G8qOd</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2402505779</pqid></control><display><type>article</type><title>Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Huge, Nicole ; Sandbothe, Maria ; Schröder, Anna K. ; Stalke, Amelie ; Eilers, Marlies ; Schäffer, Vera ; Schlegelberger, Brigitte ; Illig, Thomas ; Vajen, Beate ; Skawran, Britta</creator><creatorcontrib>Huge, Nicole ; Sandbothe, Maria ; Schröder, Anna K. ; Stalke, Amelie ; Eilers, Marlies ; Schäffer, Vera ; Schlegelberger, Brigitte ; Illig, Thomas ; Vajen, Beate ; Skawran, Britta</creatorcontrib><description>Background
Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.
Methods
Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.
Results
Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of
BCL9
and
BCL9L
was upregulated in human HCC and increased with progressing dedifferentiation. For
BCL9L
, higher expression was observed in tumors of larger size. Overexpression of
BCL9
and
BCL9L
correlated with poor overall survival, especially in HCC without activated Wnt signaling.
Conclusion
Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
Graphic abstract</description><identifier>ISSN: 1936-0533</identifier><identifier>EISSN: 1936-0541</identifier><identifier>DOI: 10.1007/s12072-019-09977-w</identifier><identifier>PMID: 31440992</identifier><language>eng</language><publisher>New Delhi: Springer India</publisher><subject>Apoptosis ; beta Catenin - metabolism ; Biotechnology ; Cancer ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - mortality ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Cell viability ; Colorectal Surgery ; DNA-Binding Proteins - genetics ; Gene Expression Regulation, Neoplastic ; Hepatocellular carcinoma ; Hepatocytes ; Hepatology ; Homology ; Humans ; Liver cancer ; Liver Neoplasms - genetics ; Liver Neoplasms - mortality ; Liver Neoplasms - pathology ; Medicine ; Medicine & Public Health ; Neoplasm Proteins ; Original ; Original Article ; Pharmacogenetics ; Prognosis ; Signal transduction ; Signaling ; siRNA ; Surgery ; Survival ; Survival Analysis ; Transcription Factors - genetics ; Tumors ; Wnt protein ; Wnt Signaling Pathway ; β-Catenin</subject><ispartof>Hepatology international, 2020-05, Vol.14 (3), p.373-384</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019. This work 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-c474t-51cfdab3bf6023dcb7dbab532f339e0b49b6acf001af4aa9c321cedef5fe89fb3</citedby><cites>FETCH-LOGICAL-c474t-51cfdab3bf6023dcb7dbab532f339e0b49b6acf001af4aa9c321cedef5fe89fb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12072-019-09977-w$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12072-019-09977-w$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31440992$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huge, Nicole</creatorcontrib><creatorcontrib>Sandbothe, Maria</creatorcontrib><creatorcontrib>Schröder, Anna K.</creatorcontrib><creatorcontrib>Stalke, Amelie</creatorcontrib><creatorcontrib>Eilers, Marlies</creatorcontrib><creatorcontrib>Schäffer, Vera</creatorcontrib><creatorcontrib>Schlegelberger, Brigitte</creatorcontrib><creatorcontrib>Illig, Thomas</creatorcontrib><creatorcontrib>Vajen, Beate</creatorcontrib><creatorcontrib>Skawran, Britta</creatorcontrib><title>Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma</title><title>Hepatology international</title><addtitle>Hepatol Int</addtitle><addtitle>Hepatol Int</addtitle><description>Background
Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.
Methods
Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.
Results
Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of
BCL9
and
BCL9L
was upregulated in human HCC and increased with progressing dedifferentiation. For
BCL9L
, higher expression was observed in tumors of larger size. Overexpression of
BCL9
and
BCL9L
correlated with poor overall survival, especially in HCC without activated Wnt signaling.
Conclusion
Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
Graphic abstract</description><subject>Apoptosis</subject><subject>beta Catenin - metabolism</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - mortality</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Survival</subject><subject>Cell viability</subject><subject>Colorectal Surgery</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatology</subject><subject>Homology</subject><subject>Humans</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - mortality</subject><subject>Liver Neoplasms - pathology</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neoplasm Proteins</subject><subject>Original</subject><subject>Original Article</subject><subject>Pharmacogenetics</subject><subject>Prognosis</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Surgery</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Transcription Factors - genetics</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway</subject><subject>β-Catenin</subject><issn>1936-0533</issn><issn>1936-0541</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9UcFu1DAQtRCIlsIP9FBF4sIlMLaTuL5UKitokVZCSK04WmNnvE2Vtbd2QsXf4-2WLXDgNKOZ997M02PsmMN7DqA-ZC5AiRq4rkFrper7Z-yQa9nV0Db8-b6X8oC9yvkWoG073r1kB5I3TaGIQ_bte5iqPOE057qnDYWeyiAGF1cUBlelOFIVffVxsdQVhv6hWVZDqG5og1N0NI7ziKlymNwQ4hpfsxcex0xvHusRu_786WpxWS-_XnxZnC9r16hmqlvufI9WWt-BkL2zqrdoWym8lJrANtp26DwAR98gaicFd9STbz2dam_lETvb6W5mu6belb8TjmaThjWmnybiYP7ehOHGrOIPo4SAU62LwLtHgRTvZsqTWQ956wcDxTkbIWWnNXS6K9C3_0Bv45xCsWdEA6KFVqmtoNihXIo5J_L7ZziYbWJml5gpiZmHxMx9IZ38aWNP-R1RAcgdIJdVWFF6uv0f2V9G8qOd</recordid><startdate>20200501</startdate><enddate>20200501</enddate><creator>Huge, Nicole</creator><creator>Sandbothe, Maria</creator><creator>Schröder, Anna K.</creator><creator>Stalke, Amelie</creator><creator>Eilers, Marlies</creator><creator>Schäffer, Vera</creator><creator>Schlegelberger, Brigitte</creator><creator>Illig, Thomas</creator><creator>Vajen, Beate</creator><creator>Skawran, Britta</creator><general>Springer India</general><general>Springer Nature B.V</general><scope>C6C</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>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200501</creationdate><title>Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma</title><author>Huge, Nicole ; Sandbothe, Maria ; Schröder, Anna K. ; Stalke, Amelie ; Eilers, Marlies ; Schäffer, Vera ; Schlegelberger, Brigitte ; Illig, Thomas ; Vajen, Beate ; Skawran, Britta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-51cfdab3bf6023dcb7dbab532f339e0b49b6acf001af4aa9c321cedef5fe89fb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Apoptosis</topic><topic>beta Catenin - metabolism</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - mortality</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Survival</topic><topic>Cell viability</topic><topic>Colorectal Surgery</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Hepatology</topic><topic>Homology</topic><topic>Humans</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - mortality</topic><topic>Liver Neoplasms - pathology</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neoplasm Proteins</topic><topic>Original</topic><topic>Original Article</topic><topic>Pharmacogenetics</topic><topic>Prognosis</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>siRNA</topic><topic>Surgery</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Transcription Factors - genetics</topic><topic>Tumors</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huge, Nicole</creatorcontrib><creatorcontrib>Sandbothe, Maria</creatorcontrib><creatorcontrib>Schröder, Anna K.</creatorcontrib><creatorcontrib>Stalke, Amelie</creatorcontrib><creatorcontrib>Eilers, Marlies</creatorcontrib><creatorcontrib>Schäffer, Vera</creatorcontrib><creatorcontrib>Schlegelberger, Brigitte</creatorcontrib><creatorcontrib>Illig, Thomas</creatorcontrib><creatorcontrib>Vajen, Beate</creatorcontrib><creatorcontrib>Skawran, Britta</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hepatology international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huge, Nicole</au><au>Sandbothe, Maria</au><au>Schröder, Anna K.</au><au>Stalke, Amelie</au><au>Eilers, Marlies</au><au>Schäffer, Vera</au><au>Schlegelberger, Brigitte</au><au>Illig, Thomas</au><au>Vajen, Beate</au><au>Skawran, Britta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma</atitle><jtitle>Hepatology international</jtitle><stitle>Hepatol Int</stitle><addtitle>Hepatol Int</addtitle><date>2020-05-01</date><risdate>2020</risdate><volume>14</volume><issue>3</issue><spage>373</spage><epage>384</epage><pages>373-384</pages><issn>1936-0533</issn><eissn>1936-0541</eissn><abstract>Background
Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.
Methods
Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.
Results
Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of
BCL9
and
BCL9L
was upregulated in human HCC and increased with progressing dedifferentiation. For
BCL9L
, higher expression was observed in tumors of larger size. Overexpression of
BCL9
and
BCL9L
correlated with poor overall survival, especially in HCC without activated Wnt signaling.
Conclusion
Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
Graphic abstract</abstract><cop>New Delhi</cop><pub>Springer India</pub><pmid>31440992</pmid><doi>10.1007/s12072-019-09977-w</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; SpringerLink Journals |
| subjects | Apoptosis beta Catenin - metabolism Biotechnology Cancer Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - mortality Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell Proliferation Cell Survival Cell viability Colorectal Surgery DNA-Binding Proteins - genetics Gene Expression Regulation, Neoplastic Hepatocellular carcinoma Hepatocytes Hepatology Homology Humans Liver cancer Liver Neoplasms - genetics Liver Neoplasms - mortality Liver Neoplasms - pathology Medicine Medicine & Public Health Neoplasm Proteins Original Original Article Pharmacogenetics Prognosis Signal transduction Signaling siRNA Surgery Survival Survival Analysis Transcription Factors - genetics Tumors Wnt protein Wnt Signaling Pathway β-Catenin |
| title | Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma |
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