Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein
A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV‐associated hepatocarcinogenesis attracted...
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| Veröffentlicht in: | Cancer science 2012-12, Vol.103 (12), p.2072-2081 |
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| creator | Liu, Haiou Xu, Le He, Hongyong Zhu, Yu Liu, Jing Wang, Shanshan Chen, Lin Wu, Qian Xu, Jiejie Gu, Jianxin |
| description | A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV‐associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce epithelial–mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/AKT/GSK‐3β) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK‐3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HBx in promoting epithelial–mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK‐3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV‐associated HCC patients. |
| doi_str_mv | 10.1111/cas.12017 |
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| fullrecord | <record><control><sourceid>proquest_24P</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7659259</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1285089034</sourcerecordid><originalsourceid>FETCH-LOGICAL-j3987-8dd040f7ba47c6fa37cc81c9e8cca1b378cd97d0cf70b3859108fdf19a04bf553</originalsourceid><addsrcrecordid>eNqNkV1LwzAUhoMobn5c-Ackl950S5q2SW6EOdQJAy-m4F1I03TLaNPZtJP56033hd55OHBeOA8vJ3kBuMFogH0NlXQDHCJMT0Afk4gHFKHkdKtpwBEJe-DCuSVCJIl4dA56YchjShPSB_OJXsnGNMbBB7g2devgB1zVVaON7WbplYOLDqpKCZUuCmjsWjpTWShtBkvdSOfbG6Qb6FVqCvNt7BzOrDTFwesKnOWycPp6Py_B-9Pj23gSTF-fX8ajabAknNGAZRmKUE5TGVGV5JJQpRhWXDOlJE4JZSrjNEMqpyglLOYYsTzLMZcoSvM4Jpfgfue7atNSZ0rbppaFWNWmlPVGVNKIvxtrFmJerQVNYh7G3Bvc7Q3q6rPVrhGlcd2zpdVV6wQOWYyY_9ToH2joKUQj7NHb32cd7zkE4YHhDvgyhd4c9xiJLmHhExbbhMV4NNsK8gNOzJsE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1223430741</pqid></control><display><type>article</type><title>Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein</title><source>Wiley-Blackwell Open Access Titles</source><creator>Liu, Haiou ; Xu, Le ; He, Hongyong ; Zhu, Yu ; Liu, Jing ; Wang, Shanshan ; Chen, Lin ; Wu, Qian ; Xu, Jiejie ; Gu, Jianxin</creator><creatorcontrib>Liu, Haiou ; Xu, Le ; He, Hongyong ; Zhu, Yu ; Liu, Jing ; Wang, Shanshan ; Chen, Lin ; Wu, Qian ; Xu, Jiejie ; Gu, Jianxin</creatorcontrib><description>A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV‐associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce epithelial–mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/AKT/GSK‐3β) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK‐3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HBx in promoting epithelial–mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK‐3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV‐associated HCC patients.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.12017</identifier><identifier>PMID: 22957763</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; 3-Phosphoinositide-Dependent Protein Kinases ; AKT protein ; Animal models ; Animals ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell migration ; Cell Movement ; Chronic infection ; Epithelial-Mesenchymal Transition ; Glycogen synthase kinase 3 ; Hepatitis B virus ; Hepatitis B virus - metabolism ; Hepatitis B virus - pathogenicity ; Hepatocellular carcinoma ; Hepatoma ; Humans ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Lung ; Male ; Metastases ; Mice ; Mice, Nude ; Molecular modelling ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Original ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Signal Transduction ; Snail Family Transcription Factors ; snail protein ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transfection ; Tumors ; Viral Proteins - genetics ; Viral Proteins - metabolism ; X protein</subject><ispartof>Cancer science, 2012-12, Vol.103 (12), p.2072-2081</ispartof><rights>2012 Japanese Cancer Association</rights><rights>2012 Japanese Cancer Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659259/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659259/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fcas.12017$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22957763$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Haiou</creatorcontrib><creatorcontrib>Xu, Le</creatorcontrib><creatorcontrib>He, Hongyong</creatorcontrib><creatorcontrib>Zhu, Yu</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Wang, Shanshan</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Wu, Qian</creatorcontrib><creatorcontrib>Xu, Jiejie</creatorcontrib><creatorcontrib>Gu, Jianxin</creatorcontrib><title>Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV‐associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce epithelial–mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/AKT/GSK‐3β) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK‐3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HBx in promoting epithelial–mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK‐3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV‐associated HCC patients.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>3-Phosphoinositide-Dependent Protein Kinases</subject><subject>AKT protein</subject><subject>Animal models</subject><subject>Animals</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Chronic infection</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Glycogen synthase kinase 3</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B virus - metabolism</subject><subject>Hepatitis B virus - pathogenicity</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatoma</subject><subject>Humans</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Lung</subject><subject>Male</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular modelling</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>Original</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Signal Transduction</subject><subject>Snail Family Transcription Factors</subject><subject>snail protein</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><subject>Tumors</subject><subject>Viral Proteins - genetics</subject><subject>Viral Proteins - metabolism</subject><subject>X protein</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkV1LwzAUhoMobn5c-Ackl950S5q2SW6EOdQJAy-m4F1I03TLaNPZtJP56033hd55OHBeOA8vJ3kBuMFogH0NlXQDHCJMT0Afk4gHFKHkdKtpwBEJe-DCuSVCJIl4dA56YchjShPSB_OJXsnGNMbBB7g2devgB1zVVaON7WbplYOLDqpKCZUuCmjsWjpTWShtBkvdSOfbG6Qb6FVqCvNt7BzOrDTFwesKnOWycPp6Py_B-9Pj23gSTF-fX8ajabAknNGAZRmKUE5TGVGV5JJQpRhWXDOlJE4JZSrjNEMqpyglLOYYsTzLMZcoSvM4Jpfgfue7atNSZ0rbppaFWNWmlPVGVNKIvxtrFmJerQVNYh7G3Bvc7Q3q6rPVrhGlcd2zpdVV6wQOWYyY_9ToH2joKUQj7NHb32cd7zkE4YHhDvgyhd4c9xiJLmHhExbbhMV4NNsK8gNOzJsE</recordid><startdate>201212</startdate><enddate>201212</enddate><creator>Liu, Haiou</creator><creator>Xu, Le</creator><creator>He, Hongyong</creator><creator>Zhu, Yu</creator><creator>Liu, Jing</creator><creator>Wang, Shanshan</creator><creator>Chen, Lin</creator><creator>Wu, Qian</creator><creator>Xu, Jiejie</creator><creator>Gu, Jianxin</creator><general>John Wiley and Sons Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7U9</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201212</creationdate><title>Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein</title><author>Liu, Haiou ; Xu, Le ; He, Hongyong ; Zhu, Yu ; Liu, Jing ; Wang, Shanshan ; Chen, Lin ; Wu, Qian ; Xu, Jiejie ; Gu, Jianxin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3987-8dd040f7ba47c6fa37cc81c9e8cca1b378cd97d0cf70b3859108fdf19a04bf553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>3-Phosphoinositide-Dependent Protein Kinases</topic><topic>AKT protein</topic><topic>Animal models</topic><topic>Animals</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement</topic><topic>Chronic infection</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Glycogen synthase kinase 3</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B virus - metabolism</topic><topic>Hepatitis B virus - pathogenicity</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatoma</topic><topic>Humans</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Lung</topic><topic>Male</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular modelling</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Metastasis</topic><topic>Original</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Signal Transduction</topic><topic>Snail Family Transcription Factors</topic><topic>snail protein</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><topic>Tumors</topic><topic>Viral Proteins - genetics</topic><topic>Viral Proteins - metabolism</topic><topic>X protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Haiou</creatorcontrib><creatorcontrib>Xu, Le</creatorcontrib><creatorcontrib>He, Hongyong</creatorcontrib><creatorcontrib>Zhu, Yu</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Wang, Shanshan</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Wu, Qian</creatorcontrib><creatorcontrib>Xu, Jiejie</creatorcontrib><creatorcontrib>Gu, Jianxin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Liu, Haiou</au><au>Xu, Le</au><au>He, Hongyong</au><au>Zhu, Yu</au><au>Liu, Jing</au><au>Wang, Shanshan</au><au>Chen, Lin</au><au>Wu, Qian</au><au>Xu, Jiejie</au><au>Gu, Jianxin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2012-12</date><risdate>2012</risdate><volume>103</volume><issue>12</issue><spage>2072</spage><epage>2081</epage><pages>2072-2081</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV‐associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce epithelial–mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/AKT/GSK‐3β) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK‐3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HBx in promoting epithelial–mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK‐3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV‐associated HCC patients.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>22957763</pmid><doi>10.1111/cas.12017</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase 3-Phosphoinositide-Dependent Protein Kinases AKT protein Animal models Animals Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell migration Cell Movement Chronic infection Epithelial-Mesenchymal Transition Glycogen synthase kinase 3 Hepatitis B virus Hepatitis B virus - metabolism Hepatitis B virus - pathogenicity Hepatocellular carcinoma Hepatoma Humans Liver Neoplasms - metabolism Liver Neoplasms - pathology Lung Male Metastases Mice Mice, Nude Molecular modelling Neoplasm Invasiveness Neoplasm Metastasis Original Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Signal Transduction Snail Family Transcription Factors snail protein Trans-Activators - genetics Trans-Activators - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transfection Tumors Viral Proteins - genetics Viral Proteins - metabolism X protein |
| title | Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein |
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