Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV p...
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| Veröffentlicht in: | PloS one 2011-12, Vol.6 (12), p.e28977 |
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| creator | Hung, Jui-Hsiang Teng, Yen-Ni Wang, Lily Hui-Ching Su, Ih-Jen Wang, Clay C C Huang, Wenya Lee, Kuan-Han Lu, Kuan-Ying Wang, Lyu-Han |
| description | Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear.
Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p=0.05) and protein (3.2±0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.
Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor. |
| doi_str_mv | 10.1371/journal.pone.0028977 |
| format | Article |
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Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p=0.05) and protein (3.2±0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.
Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0028977</identifier><identifier>PMID: 22216150</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; AKT protein ; Animals ; Antimetabolites, Antineoplastic - pharmacology ; Apoptosis ; Base Sequence ; Bcl-2 protein ; Bcl-x protein ; Biology ; Caspase ; Caspase 3 - metabolism ; Caspase-3 ; Cell death ; Cell Line, Tumor ; Cell surface ; Chemotherapy ; Colonies ; Disease resistance ; DNA Primers ; Drug resistance ; Drug Resistance, Neoplasm ; Fluorouracil ; Fluorouracil - pharmacology ; Genetic engineering ; Hepatitis ; Hepatitis B ; Hepatitis B Surface Antigens - genetics ; Hepatitis B Surface Antigens - metabolism ; Hepatitis B virus ; Hepatocellular carcinoma ; Immunohistochemistry ; Kinases ; Liver ; Liver cancer ; Mcl-1 protein ; Medicine ; Mice ; Mice, Transgenic ; mRNA ; Mutation ; NF-kappa B - metabolism ; NF-κB protein ; Phosphorylation ; Polymerase Chain Reaction ; Protein folding ; Protein Kinases - metabolism ; Protein Precursors - genetics ; Protein Precursors - metabolism ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Radiation therapy ; RNA ; Transgenic mice ; Viruses</subject><ispartof>PloS one, 2011-12, Vol.6 (12), p.e28977</ispartof><rights>2011 Hung et al.</rights><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Hung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Hung et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-b0e91744de8492713c242154a32277dc5f518aade9a0bf9ee8623d13ddc8785e3</citedby><cites>FETCH-LOGICAL-c691t-b0e91744de8492713c242154a32277dc5f518aade9a0bf9ee8623d13ddc8785e3</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/PMC3245229/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245229/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22216150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Afford, Simon</contributor><creatorcontrib>Hung, Jui-Hsiang</creatorcontrib><creatorcontrib>Teng, Yen-Ni</creatorcontrib><creatorcontrib>Wang, Lily Hui-Ching</creatorcontrib><creatorcontrib>Su, Ih-Jen</creatorcontrib><creatorcontrib>Wang, Clay C C</creatorcontrib><creatorcontrib>Huang, Wenya</creatorcontrib><creatorcontrib>Lee, Kuan-Han</creatorcontrib><creatorcontrib>Lu, Kuan-Ying</creatorcontrib><creatorcontrib>Wang, Lyu-Han</creatorcontrib><title>Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear.
Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p=0.05) and protein (3.2±0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.
Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor.</description><subject>5-Fluorouracil</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Apoptosis</subject><subject>Base Sequence</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>Biology</subject><subject>Caspase</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase-3</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell surface</subject><subject>Chemotherapy</subject><subject>Colonies</subject><subject>Disease resistance</subject><subject>DNA Primers</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Fluorouracil</subject><subject>Fluorouracil - pharmacology</subject><subject>Genetic engineering</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B Surface Antigens - genetics</subject><subject>Hepatitis B Surface Antigens - metabolism</subject><subject>Hepatitis B virus</subject><subject>Hepatocellular carcinoma</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Mcl-1 protein</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>mRNA</subject><subject>Mutation</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Phosphorylation</subject><subject>Polymerase Chain Reaction</subject><subject>Protein folding</subject><subject>Protein Kinases - metabolism</subject><subject>Protein Precursors - genetics</subject><subject>Protein Precursors - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Radiation therapy</subject><subject>RNA</subject><subject>Transgenic mice</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1GL1DAQx4so3nn6DUQDguBD1yZp0_ZFuDvUWzg48NTXME2nu1nSZi9Jj7vv4Ic26_aOLShIHhpmfvPP9M9Mkrym2YLykn7c2NENYBZbO-Aiy1hVl-WT5JjWnKWCZfzpwf0oeeH9JssKXgnxPDlijFFBi-w4-bUc2lEFbQdiO3KmTMoI3m0der-LNfdkjVsIOmhPzsitdqMnMZteM9KPAYZADLgVEj-6DhTGnA2oBxIFtI_5GAqWFGlnRutix6C0IcEhhB5jcSQvxnVaEoXG-JfJsw6Mx1fT9yT58eXz9_OL9PLq6_L89DJVoqYhbTKsaZnnLVZ5zUrKFcsZLXLgjJVlq4quoBVAizVkTVcjVoLxlvK2VVVZFchPkrd73a2xXk5Gekk5jbbkXIhILPdEa2Ejt0734O6lBS3_BKxbSXBBK4MSCoFcZCBEQ3NRZtBQVjCApu4a0ag6an2aXhubHlsV_9uBmYnOM4Ney5W9lZzlBWM7gXeTgLM3I_rwj5YnagWxKz10NoqpXnslT_NSVEVF6zxSi79Q8bTYaxVHqdMxPiv4MCuITMC7sILRe7m8_vb_7NXPOfv-gF0jmLD21oy7UfRzMN-DylnvHXaPztFM7jbhwQ252wQ5bUIse3Po-mPRw-jz34MoBLE</recordid><startdate>20111222</startdate><enddate>20111222</enddate><creator>Hung, Jui-Hsiang</creator><creator>Teng, Yen-Ni</creator><creator>Wang, Lily Hui-Ching</creator><creator>Su, Ih-Jen</creator><creator>Wang, Clay C C</creator><creator>Huang, Wenya</creator><creator>Lee, Kuan-Han</creator><creator>Lu, Kuan-Ying</creator><creator>Wang, Lyu-Han</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20111222</creationdate><title>Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells</title><author>Hung, Jui-Hsiang ; Teng, Yen-Ni ; Wang, Lily Hui-Ching ; Su, Ih-Jen ; Wang, Clay C C ; Huang, Wenya ; Lee, Kuan-Han ; Lu, Kuan-Ying ; Wang, Lyu-Han</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-b0e91744de8492713c242154a32277dc5f518aade9a0bf9ee8623d13ddc8785e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>5-Fluorouracil</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Apoptosis</topic><topic>Base Sequence</topic><topic>Bcl-2 protein</topic><topic>Bcl-x protein</topic><topic>Biology</topic><topic>Caspase</topic><topic>Caspase 3 - metabolism</topic><topic>Caspase-3</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell surface</topic><topic>Chemotherapy</topic><topic>Colonies</topic><topic>Disease resistance</topic><topic>DNA Primers</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Fluorouracil</topic><topic>Fluorouracil - pharmacology</topic><topic>Genetic engineering</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B Surface Antigens - genetics</topic><topic>Hepatitis B Surface Antigens - metabolism</topic><topic>Hepatitis B virus</topic><topic>Hepatocellular carcinoma</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Mcl-1 protein</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>mRNA</topic><topic>Mutation</topic><topic>NF-kappa B - 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Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear.
Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p=0.05) and protein (3.2±0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.
Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22216150</pmid><doi>10.1371/journal.pone.0028977</doi><tpages>e28977</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-12, Vol.6 (12), p.e28977 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1312164366 |
| source | MEDLINE; Public Library of Science (PLoS) Journals Open Access; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 5-Fluorouracil AKT protein Animals Antimetabolites, Antineoplastic - pharmacology Apoptosis Base Sequence Bcl-2 protein Bcl-x protein Biology Caspase Caspase 3 - metabolism Caspase-3 Cell death Cell Line, Tumor Cell surface Chemotherapy Colonies Disease resistance DNA Primers Drug resistance Drug Resistance, Neoplasm Fluorouracil Fluorouracil - pharmacology Genetic engineering Hepatitis Hepatitis B Hepatitis B Surface Antigens - genetics Hepatitis B Surface Antigens - metabolism Hepatitis B virus Hepatocellular carcinoma Immunohistochemistry Kinases Liver Liver cancer Mcl-1 protein Medicine Mice Mice, Transgenic mRNA Mutation NF-kappa B - metabolism NF-κB protein Phosphorylation Polymerase Chain Reaction Protein folding Protein Kinases - metabolism Protein Precursors - genetics Protein Precursors - metabolism Proto-Oncogene Proteins c-bcl-2 - metabolism Radiation therapy RNA Transgenic mice Viruses |
| title | Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-10T06%3A30%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Induction%20of%20Bcl-2%20expression%20by%20hepatitis%20B%20virus%20pre-S2%20mutant%20large%20surface%20protein%20resistance%20to%205-fluorouracil%20treatment%20in%20Huh-7%20cells&rft.jtitle=PloS%20one&rft.au=Hung,%20Jui-Hsiang&rft.date=2011-12-22&rft.volume=6&rft.issue=12&rft.spage=e28977&rft.pages=e28977-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0028977&rft_dat=%3Cgale_plos_%3EA476858194%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1312164366&rft_id=info:pmid/22216150&rft_galeid=A476858194&rft_doaj_id=oai_doaj_org_article_a56e360a66b14670ab1252aab9fb6bc9&rfr_iscdi=true |