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Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect ce...
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| Published in: | PloS one 2016-04, Vol.11 (4), p.e0153863-e0153863 |
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| creator | Ren, Jianwai Chen, George G Liu, Yi Su, Xianwei Hu, Baoguang Leung, Billy C S Wang, Y Ho, Rocky L K Yang, Shengli Lu, Gang Lee, C G Lai, Paul B S |
| description | Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy. |
| doi_str_mv | 10.1371/journal.pone.0153863 |
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It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0153863</identifier><identifier>PMID: 27093553</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>17β-Estradiol ; Angiogenesis ; Animal tissues ; Animals ; Anticancer properties ; Apoptosis ; Apoptosis - drug effects ; Biology and Life Sciences ; Cancer ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - metabolism ; Cell cycle ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; CYP1A2 protein ; Cytochrome ; Cytochrome P-450 CYP1A2 - metabolism ; Cytochrome P450 ; Cytotoxicity ; Enzymes ; Estradiol - analogs & derivatives ; Estradiol - metabolism ; Estrogen Receptor alpha - metabolism ; Estrogen Receptor beta - metabolism ; Estrogen receptors ; Estrogens ; Estrogens - metabolism ; Gastroenterology ; Gender ; Hepatocellular carcinoma ; Hepatocytes ; Histone deacetylase ; Humans ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver cancer ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Male ; Malignancy ; Medical research ; Medicine ; Medicine and Health Sciences ; Metabolism ; Metabolites ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; p53 Protein ; Phenylurea Compounds - pharmacology ; R&D ; Receptors ; Receptors, Estrogen - metabolism ; Research & development ; Research and Analysis Methods ; Rodents ; Sex hormones ; Surgery ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - metabolism ; Xenografts</subject><ispartof>PloS one, 2016-04, Vol.11 (4), p.e0153863-e0153863</ispartof><rights>2016 Ren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2016 Ren et al 2016 Ren et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-f469cb9011fc465291ab611003b503127d04b790c1212ae88f6dc5460b13a8143</citedby><cites>FETCH-LOGICAL-c456t-f469cb9011fc465291ab611003b503127d04b790c1212ae88f6dc5460b13a8143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1782205402/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1782205402?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27093553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gong, Zhiyuan</contributor><creatorcontrib>Ren, Jianwai</creatorcontrib><creatorcontrib>Chen, George G</creatorcontrib><creatorcontrib>Liu, Yi</creatorcontrib><creatorcontrib>Su, Xianwei</creatorcontrib><creatorcontrib>Hu, Baoguang</creatorcontrib><creatorcontrib>Leung, Billy C S</creatorcontrib><creatorcontrib>Wang, Y</creatorcontrib><creatorcontrib>Ho, Rocky L K</creatorcontrib><creatorcontrib>Yang, Shengli</creatorcontrib><creatorcontrib>Lu, Gang</creatorcontrib><creatorcontrib>Lee, C G</creatorcontrib><creatorcontrib>Lai, Paul B S</creatorcontrib><title>Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.</description><subject>17β-Estradiol</subject><subject>Angiogenesis</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biology and Life Sciences</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>CYP1A2 protein</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP1A2 - metabolism</subject><subject>Cytochrome P450</subject><subject>Cytotoxicity</subject><subject>Enzymes</subject><subject>Estradiol - analogs & derivatives</subject><subject>Estradiol - metabolism</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Estrogen Receptor beta - metabolism</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Estrogens - metabolism</subject><subject>Gastroenterology</subject><subject>Gender</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Histone deacetylase</subject><subject>Humans</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - metabolism</subject><subject>Male</subject><subject>Malignancy</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>p53 Protein</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>R&D</subject><subject>Receptors</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Research & development</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Sex hormones</subject><subject>Surgery</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1TAUtBCIlrZ_gCASGza5nONXkg1SdVVopSKQ2q4tx3HaXDlxsJNK5bP4EL4J3960ahErW_bMnDmjIeQtwgpZgZ82fg6DdqvRD3YFKFgp2QuyjxWjuaTAXj6575E3MW4AtiD5muzRAiomBNsnF-u7yZub4Hub_eACMjym2Tc76dq77peNGRZ_fucncQq66bzLJp9dzOMYbIzZqR11IlvnZqdDttbBdIPv9SF51WoX7dFyHpCrLyeX69P8_PvXs_XxeW64kFPeclmZugLE1nApaIW6logArBbAkBYN8LqowCBFqm1ZtrIxgkuokekSOTsg73e6o_NRLXlEhUVJKQgONCHOdojG640aQ9frcKe87tT9gw_XSoepM84qy5tC8IaXTW04TW6kMUXyxikYbQ0krc_LtLnubWPskDJxz0Sf_wzdjbr2t4qXTCalJPBxEQj-52zjpPoubtPTg_XzvW_GODBeJeiHf6D_347vUCb4GINtH80gqG1HHlhq2xG1dCTR3j1d5JH0UAr2F5yEuHk</recordid><startdate>20160419</startdate><enddate>20160419</enddate><creator>Ren, Jianwai</creator><creator>Chen, George G</creator><creator>Liu, Yi</creator><creator>Su, Xianwei</creator><creator>Hu, Baoguang</creator><creator>Leung, Billy C S</creator><creator>Wang, Y</creator><creator>Ho, Rocky L K</creator><creator>Yang, Shengli</creator><creator>Lu, Gang</creator><creator>Lee, C G</creator><creator>Lai, Paul B S</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>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>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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160419</creationdate><title>Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma</title><author>Ren, Jianwai ; Chen, George G ; Liu, Yi ; Su, Xianwei ; Hu, Baoguang ; Leung, Billy C S ; Wang, Y ; Ho, Rocky L K ; Yang, Shengli ; Lu, Gang ; Lee, C G ; Lai, Paul B S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-f469cb9011fc465291ab611003b503127d04b790c1212ae88f6dc5460b13a8143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>17β-Estradiol</topic><topic>Angiogenesis</topic><topic>Animal tissues</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biology and Life Sciences</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>CYP1A2 protein</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 CYP1A2 - metabolism</topic><topic>Cytochrome P450</topic><topic>Cytotoxicity</topic><topic>Enzymes</topic><topic>Estradiol - analogs & derivatives</topic><topic>Estradiol - metabolism</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Estrogen Receptor beta - metabolism</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Estrogens - metabolism</topic><topic>Gastroenterology</topic><topic>Gender</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Histone deacetylase</topic><topic>Humans</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ren, Jianwai</au><au>Chen, George G</au><au>Liu, Yi</au><au>Su, Xianwei</au><au>Hu, Baoguang</au><au>Leung, Billy C S</au><au>Wang, Y</au><au>Ho, Rocky L K</au><au>Yang, Shengli</au><au>Lu, Gang</au><au>Lee, C G</au><au>Lai, Paul B S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-04-19</date><risdate>2016</risdate><volume>11</volume><issue>4</issue><spage>e0153863</spage><epage>e0153863</epage><pages>e0153863-e0153863</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Conceived and designed the experiments: JR GGC PBSL. Performed the experiments: JR. Analyzed the data: JR YL YW GL CGL GGC. Wrote the paper: JR YL YW GL CGL GGC. Conducted animal work: XS BH GL. Performed qPCR and FACS: BCSL. Performed sequencing analysis: RLKH. Revised and approved the final version of this manuscript: GGC.</notes><notes>Competing Interests: The authors have declared that no competing interests exist.</notes><abstract>Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27093553</pmid><doi>10.1371/journal.pone.0153863</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-04, Vol.11 (4), p.e0153863-e0153863 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1782205402 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | 17β-Estradiol Angiogenesis Animal tissues Animals Anticancer properties Apoptosis Apoptosis - drug effects Biology and Life Sciences Cancer Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Cell cycle Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects CYP1A2 protein Cytochrome Cytochrome P-450 CYP1A2 - metabolism Cytochrome P450 Cytotoxicity Enzymes Estradiol - analogs & derivatives Estradiol - metabolism Estrogen Receptor alpha - metabolism Estrogen Receptor beta - metabolism Estrogen receptors Estrogens Estrogens - metabolism Gastroenterology Gender Hepatocellular carcinoma Hepatocytes Histone deacetylase Humans Liver Liver - drug effects Liver - metabolism Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Male Malignancy Medical research Medicine Medicine and Health Sciences Metabolism Metabolites Mice Mice, Inbred BALB C Mice, Nude Niacinamide - analogs & derivatives Niacinamide - pharmacology p53 Protein Phenylurea Compounds - pharmacology R&D Receptors Receptors, Estrogen - metabolism Research & development Research and Analysis Methods Rodents Sex hormones Surgery Tumor suppressor genes Tumor Suppressor Protein p53 - metabolism Xenografts |
| title | Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma |
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