Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus‐related hepatocarcinogenesis via protein phosphatase 2A‐B56γ‐mediated dephosphorylation of protein kinase B
Objectives Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals...
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| Veröffentlicht in: | Cell proliferation 2022-11, Vol.55 (11), p.e13304-n/a |
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| creator | Che, Lin Du, Ze‐Bang Wang, Wei‐Hua Wu, Jia‐Shen Han, Tun Chen, Yuan‐Yuan Han, Pei‐Yu Lei, Zhao Chen, Xiao‐Xuan He, Yun Xu, Ling Lin, Xu Lin, Zhong‐Ning Lin, Yu‐Chun |
| description | Objectives
Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx‐associated hepatocarcinogenesis phenotypes and mediating anti‐HBx antibody‐mediated tumour suppression remains unknown.
Materials and Methods
We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx‐Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti‐HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx‐associated hepatocarcinogenesis.
Results
Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV‐infected liver tissues and HBV‐associated HCC tissues. Our results demonstrated that HBx‐expression promotes AKT phosphorylation (p‐AKTThr308/Ser473), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV‐associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site‐directed mutagenesis (AKTT308A, AKTS473A) of p‐AKTThr308/Ser473 mimics dephosphorylation, genetics‐based B56γ overexpression, and intracellular anti‐HBx antibody inhibited cell growth, migration, and invasion in HBx‐expressing HCC cells.
Conclusions
Our results demonstrated that B56γ inhibited HBV/HBx‐dependent hepatocarcinogenesis by regulating the dephosphorylation of p‐AKTThr308/Ser473 in HCC cells. The intracellular anti‐HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV‐related HCC.
Schematic diagram of PP2A‐B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells to regulate the migration and invasion phenotypes of HBV/HBx‐related hepatocarcinogenesis. In current study, HBx‐expression induced the phosphorylation of specific AKT sites (p‐AKTThr308/Ser473) involved in mediating the migration and invasion phenotypes of HCC cells. The inducible upregulation of B56γ mediated the dephosphorylation of p‐AKTThr308 |
| doi_str_mv | 10.1111/cpr.13304 |
| format | Article |
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Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx‐associated hepatocarcinogenesis phenotypes and mediating anti‐HBx antibody‐mediated tumour suppression remains unknown.
Materials and Methods
We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx‐Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti‐HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx‐associated hepatocarcinogenesis.
Results
Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV‐infected liver tissues and HBV‐associated HCC tissues. Our results demonstrated that HBx‐expression promotes AKT phosphorylation (p‐AKTThr308/Ser473), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV‐associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site‐directed mutagenesis (AKTT308A, AKTS473A) of p‐AKTThr308/Ser473 mimics dephosphorylation, genetics‐based B56γ overexpression, and intracellular anti‐HBx antibody inhibited cell growth, migration, and invasion in HBx‐expressing HCC cells.
Conclusions
Our results demonstrated that B56γ inhibited HBV/HBx‐dependent hepatocarcinogenesis by regulating the dephosphorylation of p‐AKTThr308/Ser473 in HCC cells. The intracellular anti‐HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV‐related HCC.
Schematic diagram of PP2A‐B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells to regulate the migration and invasion phenotypes of HBV/HBx‐related hepatocarcinogenesis. In current study, HBx‐expression induced the phosphorylation of specific AKT sites (p‐AKTThr308/Ser473) involved in mediating the migration and invasion phenotypes of HCC cells. The inducible upregulation of B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells. Specific blockade of HBx‐expression via pTT5‐anti‐HBx plasmid‐mediated targeting intracellular anti‐HBx mAb production and genetic activation of B56γ would help to target the p‐AKTThr308/Ser473‐MMP2/9 signalling axis to mediate the multipattern chemoprevention and intervention in HBV/HBx‐related hepatocarcinogenesis.</description><identifier>ISSN: 0960-7722</identifier><identifier>EISSN: 1365-2184</identifier><identifier>DOI: 10.1111/cpr.13304</identifier><identifier>PMID: 35811356</identifier><language>eng</language><publisher>Chichester: John Wiley & Sons, Inc</publisher><subject>AKT protein ; Antibodies ; Bioinformatics ; Carcinogenesis ; Carcinogens ; Cell cycle ; Cell migration ; Dephosphorylation ; Ethics ; Gelatinase A ; Gelatinase B ; Gene expression ; Genetic engineering ; Genetics ; Genomes ; Hepatitis ; Hepatitis B ; Hepatitis B virus ; Inactivation ; Infections ; Intracellular ; Kinases ; Laboratory animals ; Liver cancer ; Matrix metalloproteinase ; Matrix metalloproteinases ; Metalloproteinase ; Metastases ; Metastasis ; Monoclonal antibodies ; Original ; Phenotypes ; Phosphatase ; Phosphatases ; Phosphoprotein phosphatase ; Phosphorylation ; Plasmids ; Protein kinases ; Protein phosphatase ; Proteins ; Signal transduction ; Site-directed mutagenesis ; Suppressors ; Tissues ; Transgenic mice ; Tumor suppressor genes ; Tumors ; Viral antibodies ; Viruses ; Xenografts ; Xenotransplantation</subject><ispartof>Cell proliferation, 2022-11, Vol.55 (11), p.e13304-n/a</ispartof><rights>2022 The Authors. published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.</rights><rights>COPYRIGHT 2022 John Wiley & Sons, Inc.</rights><rights>2022. 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-c4874-b8b095698a114d7293bbd7a59cbc24d982b5576a1122459950dc89ae70ade7463</citedby><cites>FETCH-LOGICAL-c4874-b8b095698a114d7293bbd7a59cbc24d982b5576a1122459950dc89ae70ade7463</cites><orcidid>0000-0002-4019-065X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628248/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628248/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,1412,11543,27905,27906,45555,45556,46033,46457,53772,53774</link.rule.ids></links><search><creatorcontrib>Che, Lin</creatorcontrib><creatorcontrib>Du, Ze‐Bang</creatorcontrib><creatorcontrib>Wang, Wei‐Hua</creatorcontrib><creatorcontrib>Wu, Jia‐Shen</creatorcontrib><creatorcontrib>Han, Tun</creatorcontrib><creatorcontrib>Chen, Yuan‐Yuan</creatorcontrib><creatorcontrib>Han, Pei‐Yu</creatorcontrib><creatorcontrib>Lei, Zhao</creatorcontrib><creatorcontrib>Chen, Xiao‐Xuan</creatorcontrib><creatorcontrib>He, Yun</creatorcontrib><creatorcontrib>Xu, Ling</creatorcontrib><creatorcontrib>Lin, Xu</creatorcontrib><creatorcontrib>Lin, Zhong‐Ning</creatorcontrib><creatorcontrib>Lin, Yu‐Chun</creatorcontrib><title>Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus‐related hepatocarcinogenesis via protein phosphatase 2A‐B56γ‐mediated dephosphorylation of protein kinase B</title><title>Cell proliferation</title><description>Objectives
Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx‐associated hepatocarcinogenesis phenotypes and mediating anti‐HBx antibody‐mediated tumour suppression remains unknown.
Materials and Methods
We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx‐Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti‐HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx‐associated hepatocarcinogenesis.
Results
Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV‐infected liver tissues and HBV‐associated HCC tissues. Our results demonstrated that HBx‐expression promotes AKT phosphorylation (p‐AKTThr308/Ser473), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV‐associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site‐directed mutagenesis (AKTT308A, AKTS473A) of p‐AKTThr308/Ser473 mimics dephosphorylation, genetics‐based B56γ overexpression, and intracellular anti‐HBx antibody inhibited cell growth, migration, and invasion in HBx‐expressing HCC cells.
Conclusions
Our results demonstrated that B56γ inhibited HBV/HBx‐dependent hepatocarcinogenesis by regulating the dephosphorylation of p‐AKTThr308/Ser473 in HCC cells. The intracellular anti‐HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV‐related HCC.
Schematic diagram of PP2A‐B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells to regulate the migration and invasion phenotypes of HBV/HBx‐related hepatocarcinogenesis. In current study, HBx‐expression induced the phosphorylation of specific AKT sites (p‐AKTThr308/Ser473) involved in mediating the migration and invasion phenotypes of HCC cells. The inducible upregulation of B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells. Specific blockade of HBx‐expression via pTT5‐anti‐HBx plasmid‐mediated targeting intracellular anti‐HBx mAb production and genetic activation of B56γ would help to target the p‐AKTThr308/Ser473‐MMP2/9 signalling axis to mediate the multipattern chemoprevention and intervention in HBV/HBx‐related hepatocarcinogenesis.</description><subject>AKT protein</subject><subject>Antibodies</subject><subject>Bioinformatics</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Cell cycle</subject><subject>Cell migration</subject><subject>Dephosphorylation</subject><subject>Ethics</subject><subject>Gelatinase A</subject><subject>Gelatinase B</subject><subject>Gene expression</subject><subject>Genetic engineering</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B virus</subject><subject>Inactivation</subject><subject>Infections</subject><subject>Intracellular</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Liver cancer</subject><subject>Matrix metalloproteinase</subject><subject>Matrix metalloproteinases</subject><subject>Metalloproteinase</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Monoclonal antibodies</subject><subject>Original</subject><subject>Phenotypes</subject><subject>Phosphatase</subject><subject>Phosphatases</subject><subject>Phosphoprotein phosphatase</subject><subject>Phosphorylation</subject><subject>Plasmids</subject><subject>Protein kinases</subject><subject>Protein phosphatase</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Site-directed mutagenesis</subject><subject>Suppressors</subject><subject>Tissues</subject><subject>Transgenic mice</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Viral antibodies</subject><subject>Viruses</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>0960-7722</issn><issn>1365-2184</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kk9u1DAUxiMEoqWw4AaR2NDFTP0_zgZpZgS0UiUQgrXl2G9mXDJ2sJOB2XEE7sI94A6cBKepiorAtvRkv9_3yfZ7RfEUoznO48x0cY4pRexecYyp4DOCJbtfHKNaoFlVEXJUPErpCiFMcSUeFkeUS4wpF8fFzwvfR22gbYdWx1L73jXBHspexw30zm_K8-WXMg1dFyElSKXze51c8Bm15Q56nfJy43m5hU73rs-bZbl3cUi_vn6L0Ooe7JQLRkfjfNiAh1Gzd7rsYughi7ttSN1WZzMoySIrl1z8-J7jDqy7trAwMSEesud4hbC-lX90flQuHxcP1rpN8OQmnhQfXr18vzqfXb55fbFaXM4MkxWbNbJBNRe11BgzW5GaNo2tNK9NYwiztSQN55XIWUIYr2uOrJG1hgppCxUT9KR4Mfl2Q5NvaGD8xlZ10e10PKignbqb8W6rNmGvakEkYTIbPL8xiOHTAKlXO5fGOmgPYUiKCCmRFJTxjD77C70KQ_T5eYpUFCOaa87-UBvdgnJ-HcbCjqZqUTGMCJEcZ2r-DypPCztngoe1y-d3BKeTwMSQUoT17RsxUmP3qdx96rr7Mns2sZ-zyeH_oFq9fTcpfgMcJeIv</recordid><startdate>202211</startdate><enddate>202211</enddate><creator>Che, Lin</creator><creator>Du, Ze‐Bang</creator><creator>Wang, Wei‐Hua</creator><creator>Wu, Jia‐Shen</creator><creator>Han, Tun</creator><creator>Chen, Yuan‐Yuan</creator><creator>Han, Pei‐Yu</creator><creator>Lei, Zhao</creator><creator>Chen, Xiao‐Xuan</creator><creator>He, Yun</creator><creator>Xu, Ling</creator><creator>Lin, Xu</creator><creator>Lin, Zhong‐Ning</creator><creator>Lin, Yu‐Chun</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4019-065X</orcidid></search><sort><creationdate>202211</creationdate><title>Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus‐related hepatocarcinogenesis via protein phosphatase 2A‐B56γ‐mediated dephosphorylation of protein kinase B</title><author>Che, Lin ; Du, Ze‐Bang ; Wang, Wei‐Hua ; Wu, Jia‐Shen ; Han, Tun ; Chen, Yuan‐Yuan ; Han, Pei‐Yu ; Lei, Zhao ; Chen, Xiao‐Xuan ; He, Yun ; Xu, Ling ; Lin, Xu ; Lin, Zhong‐Ning ; Lin, Yu‐Chun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4874-b8b095698a114d7293bbd7a59cbc24d982b5576a1122459950dc89ae70ade7463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>AKT protein</topic><topic>Antibodies</topic><topic>Bioinformatics</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>Cell cycle</topic><topic>Cell migration</topic><topic>Dephosphorylation</topic><topic>Ethics</topic><topic>Gelatinase A</topic><topic>Gelatinase B</topic><topic>Gene expression</topic><topic>Genetic engineering</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B virus</topic><topic>Inactivation</topic><topic>Infections</topic><topic>Intracellular</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Liver cancer</topic><topic>Matrix metalloproteinase</topic><topic>Matrix metalloproteinases</topic><topic>Metalloproteinase</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Monoclonal antibodies</topic><topic>Original</topic><topic>Phenotypes</topic><topic>Phosphatase</topic><topic>Phosphatases</topic><topic>Phosphoprotein phosphatase</topic><topic>Phosphorylation</topic><topic>Plasmids</topic><topic>Protein kinases</topic><topic>Protein phosphatase</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Site-directed mutagenesis</topic><topic>Suppressors</topic><topic>Tissues</topic><topic>Transgenic mice</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><topic>Viral antibodies</topic><topic>Viruses</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Che, Lin</creatorcontrib><creatorcontrib>Du, Ze‐Bang</creatorcontrib><creatorcontrib>Wang, Wei‐Hua</creatorcontrib><creatorcontrib>Wu, Jia‐Shen</creatorcontrib><creatorcontrib>Han, Tun</creatorcontrib><creatorcontrib>Chen, Yuan‐Yuan</creatorcontrib><creatorcontrib>Han, Pei‐Yu</creatorcontrib><creatorcontrib>Lei, Zhao</creatorcontrib><creatorcontrib>Chen, Xiao‐Xuan</creatorcontrib><creatorcontrib>He, Yun</creatorcontrib><creatorcontrib>Xu, Ling</creatorcontrib><creatorcontrib>Lin, Xu</creatorcontrib><creatorcontrib>Lin, Zhong‐Ning</creatorcontrib><creatorcontrib>Lin, Yu‐Chun</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell proliferation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Che, Lin</au><au>Du, Ze‐Bang</au><au>Wang, Wei‐Hua</au><au>Wu, Jia‐Shen</au><au>Han, Tun</au><au>Chen, Yuan‐Yuan</au><au>Han, Pei‐Yu</au><au>Lei, Zhao</au><au>Chen, Xiao‐Xuan</au><au>He, Yun</au><au>Xu, Ling</au><au>Lin, Xu</au><au>Lin, Zhong‐Ning</au><au>Lin, Yu‐Chun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus‐related hepatocarcinogenesis via protein phosphatase 2A‐B56γ‐mediated dephosphorylation of protein kinase B</atitle><jtitle>Cell proliferation</jtitle><date>2022-11</date><risdate>2022</risdate><volume>55</volume><issue>11</issue><spage>e13304</spage><epage>n/a</epage><pages>e13304-n/a</pages><issn>0960-7722</issn><eissn>1365-2184</eissn><abstract>Objectives
Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx‐associated hepatocarcinogenesis phenotypes and mediating anti‐HBx antibody‐mediated tumour suppression remains unknown.
Materials and Methods
We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx‐Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti‐HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx‐associated hepatocarcinogenesis.
Results
Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV‐infected liver tissues and HBV‐associated HCC tissues. Our results demonstrated that HBx‐expression promotes AKT phosphorylation (p‐AKTThr308/Ser473), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV‐associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site‐directed mutagenesis (AKTT308A, AKTS473A) of p‐AKTThr308/Ser473 mimics dephosphorylation, genetics‐based B56γ overexpression, and intracellular anti‐HBx antibody inhibited cell growth, migration, and invasion in HBx‐expressing HCC cells.
Conclusions
Our results demonstrated that B56γ inhibited HBV/HBx‐dependent hepatocarcinogenesis by regulating the dephosphorylation of p‐AKTThr308/Ser473 in HCC cells. The intracellular anti‐HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV‐related HCC.
Schematic diagram of PP2A‐B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells to regulate the migration and invasion phenotypes of HBV/HBx‐related hepatocarcinogenesis. In current study, HBx‐expression induced the phosphorylation of specific AKT sites (p‐AKTThr308/Ser473) involved in mediating the migration and invasion phenotypes of HCC cells. The inducible upregulation of B56γ mediated the dephosphorylation of p‐AKTThr308/Ser473 in HBx‐expressing HCC cells. Specific blockade of HBx‐expression via pTT5‐anti‐HBx plasmid‐mediated targeting intracellular anti‐HBx mAb production and genetic activation of B56γ would help to target the p‐AKTThr308/Ser473‐MMP2/9 signalling axis to mediate the multipattern chemoprevention and intervention in HBV/HBx‐related hepatocarcinogenesis.</abstract><cop>Chichester</cop><pub>John Wiley & Sons, Inc</pub><pmid>35811356</pmid><doi>10.1111/cpr.13304</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0002-4019-065X</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9628248 |
| source | DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Open Access; PubMed Central |
| subjects | AKT protein Antibodies Bioinformatics Carcinogenesis Carcinogens Cell cycle Cell migration Dephosphorylation Ethics Gelatinase A Gelatinase B Gene expression Genetic engineering Genetics Genomes Hepatitis Hepatitis B Hepatitis B virus Inactivation Infections Intracellular Kinases Laboratory animals Liver cancer Matrix metalloproteinase Matrix metalloproteinases Metalloproteinase Metastases Metastasis Monoclonal antibodies Original Phenotypes Phosphatase Phosphatases Phosphoprotein phosphatase Phosphorylation Plasmids Protein kinases Protein phosphatase Proteins Signal transduction Site-directed mutagenesis Suppressors Tissues Transgenic mice Tumor suppressor genes Tumors Viral antibodies Viruses Xenografts Xenotransplantation |
| title | Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus‐related hepatocarcinogenesis via protein phosphatase 2A‐B56γ‐mediated dephosphorylation of protein kinase B |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T21%3A19%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Intracellular%20antibody%20targeting%20HBx%20suppresses%20invasion%20and%20metastasis%20in%20hepatitis%20B%20virus%E2%80%90related%20hepatocarcinogenesis%20via%20protein%20phosphatase%202A%E2%80%90B56%CE%B3%E2%80%90mediated%20dephosphorylation%20of%20protein%20kinase%20B&rft.jtitle=Cell%20proliferation&rft.au=Che,%20Lin&rft.date=2022-11&rft.volume=55&rft.issue=11&rft.spage=e13304&rft.epage=n/a&rft.pages=e13304-n/a&rft.issn=0960-7722&rft.eissn=1365-2184&rft_id=info:doi/10.1111/cpr.13304&rft_dat=%3Cgale_pubme%3EA741022851%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2731031364&rft_id=info:pmid/35811356&rft_galeid=A741022851&rfr_iscdi=true |