Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver
Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk...
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| Veröffentlicht in: | Oncotarget 2015-04, Vol.6 (12), p.10102-10115 |
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| creator | Li, Xiaolei Tao, Junyan Cigliano, Antonio Sini, Marcella Calderaro, Julien Azoulay, Daniel Wang, Chunmei Liu, Yan Jiang, Lijie Evert, Katja Demartis, Maria I Ribback, Silvia Utpatel, Kirsten Dombrowski, Frank Evert, Matthias Calvisi, Diego F Chen, Xin |
| description | Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy. |
| doi_str_mv | 10.18632/oncotarget.3546 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4496343</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>25826091</sourcerecordid><originalsourceid>FETCH-LOGICAL-c462t-f100882deb60f003cfae71866b60edd17cb68ace31af33610f1c0a12f80b55c33</originalsourceid><addsrcrecordid>eNpVUctOwzAQtBCIVqV3Tsg_kOJH4iYXpCriUVEJDnDgFG0cuwlK4sh2KiHx8aQttGUvu96dGWt3ELqmZEZjwdmtaaXxYNfKz3gUijM0pkmYBCyK-PlJPUJT5z7JEFE4j1lyiUYsipkgCR2j79QEIH21AV-ZFhuNX5fPPF1gaAv8AR3urGmMVw4XaqNq0zWq9VtYqTrwRqq67muwO7gsTQ3tujp2fd8Y63DV4sb0Tu1QZd9Ai-tqo-wVutBQOzX9zRP0_nD_lj4Fq5fHZbpYBTIUzAeaEhLHrFC5IJoQLjWo-XACMbxVUdC5zEUMUnEKmnNBiaaSAGU6JnkUSc4n6G6v2_V5owo5rGChzjpbNWC_MgNV9n_SVmW2NpssDBPBw60A2QtIa5yzSh-4lGQ7M7KjGdnWjIFyc_rngfB3ev4DX1OMKA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver</title><source>Freely Accessible Journals</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central Open Access</source><source>PubMed Central</source><creator>Li, Xiaolei ; Tao, Junyan ; Cigliano, Antonio ; Sini, Marcella ; Calderaro, Julien ; Azoulay, Daniel ; Wang, Chunmei ; Liu, Yan ; Jiang, Lijie ; Evert, Katja ; Demartis, Maria I ; Ribback, Silvia ; Utpatel, Kirsten ; Dombrowski, Frank ; Evert, Matthias ; Calvisi, Diego F ; Chen, Xin</creator><creatorcontrib>Li, Xiaolei ; Tao, Junyan ; Cigliano, Antonio ; Sini, Marcella ; Calderaro, Julien ; Azoulay, Daniel ; Wang, Chunmei ; Liu, Yan ; Jiang, Lijie ; Evert, Katja ; Demartis, Maria I ; Ribback, Silvia ; Utpatel, Kirsten ; Dombrowski, Frank ; Evert, Matthias ; Calvisi, Diego F ; Chen, Xin</creatorcontrib><description>Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.3546</identifier><identifier>PMID: 25826091</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Proliferation - physiology ; Cholangiocarcinoma - genetics ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; Class I Phosphatidylinositol 3-Kinases ; Humans ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Liver Neoplasms, Experimental - genetics ; Liver Neoplasms, Experimental - metabolism ; Liver Neoplasms, Experimental - pathology ; Mice ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Research Paper ; Signal Transduction ; Transcription Factors ; YAP-Signaling Proteins</subject><ispartof>Oncotarget, 2015-04, Vol.6 (12), p.10102-10115</ispartof><rights>Copyright: © 2015 Li et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-f100882deb60f003cfae71866b60edd17cb68ace31af33610f1c0a12f80b55c33</citedby><cites>FETCH-LOGICAL-c462t-f100882deb60f003cfae71866b60edd17cb68ace31af33610f1c0a12f80b55c33</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/PMC4496343/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496343/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27915,27916,53782,53784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25826091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xiaolei</creatorcontrib><creatorcontrib>Tao, Junyan</creatorcontrib><creatorcontrib>Cigliano, Antonio</creatorcontrib><creatorcontrib>Sini, Marcella</creatorcontrib><creatorcontrib>Calderaro, Julien</creatorcontrib><creatorcontrib>Azoulay, Daniel</creatorcontrib><creatorcontrib>Wang, Chunmei</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Jiang, Lijie</creatorcontrib><creatorcontrib>Evert, Katja</creatorcontrib><creatorcontrib>Demartis, Maria I</creatorcontrib><creatorcontrib>Ribback, Silvia</creatorcontrib><creatorcontrib>Utpatel, Kirsten</creatorcontrib><creatorcontrib>Dombrowski, Frank</creatorcontrib><creatorcontrib>Evert, Matthias</creatorcontrib><creatorcontrib>Calvisi, Diego F</creatorcontrib><creatorcontrib>Chen, Xin</creatorcontrib><title>Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Cycle Proteins</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - physiology</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Humans</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver Neoplasms, Experimental - genetics</subject><subject>Liver Neoplasms, Experimental - metabolism</subject><subject>Liver Neoplasms, Experimental - pathology</subject><subject>Mice</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction</subject><subject>Transcription Factors</subject><subject>YAP-Signaling Proteins</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>eNpVUctOwzAQtBCIVqV3Tsg_kOJH4iYXpCriUVEJDnDgFG0cuwlK4sh2KiHx8aQttGUvu96dGWt3ELqmZEZjwdmtaaXxYNfKz3gUijM0pkmYBCyK-PlJPUJT5z7JEFE4j1lyiUYsipkgCR2j79QEIH21AV-ZFhuNX5fPPF1gaAv8AR3urGmMVw4XaqNq0zWq9VtYqTrwRqq67muwO7gsTQ3tujp2fd8Y63DV4sb0Tu1QZd9Ai-tqo-wVutBQOzX9zRP0_nD_lj4Fq5fHZbpYBTIUzAeaEhLHrFC5IJoQLjWo-XACMbxVUdC5zEUMUnEKmnNBiaaSAGU6JnkUSc4n6G6v2_V5owo5rGChzjpbNWC_MgNV9n_SVmW2NpssDBPBw60A2QtIa5yzSh-4lGQ7M7KjGdnWjIFyc_rngfB3ev4DX1OMKA</recordid><startdate>20150430</startdate><enddate>20150430</enddate><creator>Li, Xiaolei</creator><creator>Tao, Junyan</creator><creator>Cigliano, Antonio</creator><creator>Sini, Marcella</creator><creator>Calderaro, Julien</creator><creator>Azoulay, Daniel</creator><creator>Wang, Chunmei</creator><creator>Liu, Yan</creator><creator>Jiang, Lijie</creator><creator>Evert, Katja</creator><creator>Demartis, Maria I</creator><creator>Ribback, Silvia</creator><creator>Utpatel, Kirsten</creator><creator>Dombrowski, Frank</creator><creator>Evert, Matthias</creator><creator>Calvisi, Diego F</creator><creator>Chen, Xin</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>5PM</scope></search><sort><creationdate>20150430</creationdate><title>Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver</title><author>Li, Xiaolei ; Tao, Junyan ; Cigliano, Antonio ; Sini, Marcella ; Calderaro, Julien ; Azoulay, Daniel ; Wang, Chunmei ; Liu, Yan ; Jiang, Lijie ; Evert, Katja ; Demartis, Maria I ; Ribback, Silvia ; Utpatel, Kirsten ; Dombrowski, Frank ; Evert, Matthias ; Calvisi, Diego F ; Chen, Xin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-f100882deb60f003cfae71866b60edd17cb68ace31af33610f1c0a12f80b55c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Cycle Proteins</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - physiology</topic><topic>Cholangiocarcinoma - genetics</topic><topic>Cholangiocarcinoma - metabolism</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>Humans</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver Neoplasms, Experimental - genetics</topic><topic>Liver Neoplasms, Experimental - metabolism</topic><topic>Liver Neoplasms, Experimental - pathology</topic><topic>Mice</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction</topic><topic>Transcription Factors</topic><topic>YAP-Signaling Proteins</topic><toplevel>online_resources</toplevel><creatorcontrib>Li, Xiaolei</creatorcontrib><creatorcontrib>Tao, Junyan</creatorcontrib><creatorcontrib>Cigliano, Antonio</creatorcontrib><creatorcontrib>Sini, Marcella</creatorcontrib><creatorcontrib>Calderaro, Julien</creatorcontrib><creatorcontrib>Azoulay, Daniel</creatorcontrib><creatorcontrib>Wang, Chunmei</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Jiang, Lijie</creatorcontrib><creatorcontrib>Evert, Katja</creatorcontrib><creatorcontrib>Demartis, Maria I</creatorcontrib><creatorcontrib>Ribback, Silvia</creatorcontrib><creatorcontrib>Utpatel, Kirsten</creatorcontrib><creatorcontrib>Dombrowski, Frank</creatorcontrib><creatorcontrib>Evert, Matthias</creatorcontrib><creatorcontrib>Calvisi, Diego F</creatorcontrib><creatorcontrib>Chen, Xin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xiaolei</au><au>Tao, Junyan</au><au>Cigliano, Antonio</au><au>Sini, Marcella</au><au>Calderaro, Julien</au><au>Azoulay, Daniel</au><au>Wang, Chunmei</au><au>Liu, Yan</au><au>Jiang, Lijie</au><au>Evert, Katja</au><au>Demartis, Maria I</au><au>Ribback, Silvia</au><au>Utpatel, Kirsten</au><au>Dombrowski, Frank</au><au>Evert, Matthias</au><au>Calvisi, Diego F</au><au>Chen, Xin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-04-30</date><risdate>2015</risdate><volume>6</volume><issue>12</issue><spage>10102</spage><epage>10115</epage><pages>10102-10115</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>25826091</pmid><doi>10.18632/oncotarget.3546</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Cycle Proteins Cell Line, Tumor Cell Proliferation - physiology Cholangiocarcinoma - genetics Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Class I Phosphatidylinositol 3-Kinases Humans Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Liver Neoplasms, Experimental - genetics Liver Neoplasms, Experimental - metabolism Liver Neoplasms, Experimental - pathology Mice Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Research Paper Signal Transduction Transcription Factors YAP-Signaling Proteins |
| title | Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver |
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