{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:23:50Z","timestamp":1782807830171,"version":"3.54.5"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K08283"],"award-info":[{"award-number":["JP20K08283"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP25460989"],"award-info":[{"award-number":["JP25460989"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-\u03b1 promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-<jats:italic>Jun<\/jats:italic> N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-\u03b1-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) \u03b2 agonists, inhibited the TGF-\u03b1-induced cell migration whereas PPT, an ER\u03b1 agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-\u03b1-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and <jats:italic>c-Jun<\/jats:italic> N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-\u03b1. Furthermore, PHTPP, an ER\u03b2 antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-\u03b1-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-\u03b1-induced migration of HCC cells through ER\u03b2-mediated inhibition of the AKT signaling pathway.<\/jats:p>","DOI":"10.1371\/journal.pone.0262485","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T18:23:50Z","timestamp":1641839030000},"page":"e0262485","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["SERMs (selective estrogen receptor modulator), acting as estrogen receptor \u03b2 agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-\u03b1-induced migration via specific inhibition of AKT signaling pathway"],"prefix":"10.1371","volume":"17","author":[{"given":"Rie","family":"Matsushima-Nishiwaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuria","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Hosokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Tachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamitsu","family":"Hori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-6073","authenticated-orcid":true,"given":"Osamu","family":"Kozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,10]]},"reference":[{"issue":"2","key":"pone.0262485.ref001","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2174\/1574884711308020006","article-title":"The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice.","volume":"8","author":"PY Maximov","year":"2013","journal-title":"Curr Clin Pharmacol"},{"key":"pone.0262485.ref002","first-page":"1437","article-title":"Selective estrogen receptor modulators: tissue specificity and clinical utility","volume":"9","author":"S Martinkovich","year":"2014","journal-title":"Clin Interv Aging"},{"issue":"4","key":"pone.0262485.ref003","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4184\/asj.2016.10.4.787","article-title":"Selective estrogen receptor modulators","volume":"10","author":"K. An","year":"2016","journal-title":"Asian Spine J"},{"issue":"4","key":"pone.0262485.ref004","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jdiacomp.2016.12.010","article-title":"The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights.","volume":"31","author":"B Xu","year":"2017","journal-title":"J Diabetes Complications."},{"key":"pone.0262485.ref005","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma.","volume":"2","author":"JM Llovet","year":"2016","journal-title":"Nat Rev Dis Primers"},{"issue":"3","key":"pone.0262485.ref006","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin."},{"issue":"1","key":"pone.0262485.ref007","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3748\/wjg.v20.i1.142","article-title":"Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis","volume":"20","author":"Y Zhang","year":"2014","journal-title":"World J Gastroenterol"},{"issue":"31","key":"pone.0262485.ref008","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.4254\/wjh.v8.i31.1309","article-title":"Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma","volume":"8","author":"P Yang","year":"2016","journal-title":"World J Hepatol"},{"key":"pone.0262485.ref009","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.canlet.2020.02.003","article-title":"Hepatocellular carcinoma-derived exosomes in organotropic metastasis, recurrence and early diagnosis application","volume":"477","author":"Y Ge","year":"2020","journal-title":"Cancer Lett"},{"key":"pone.0262485.ref010","doi-asserted-by":"crossref","first-page":"e000107","DOI":"10.1136\/bmjgast-2016-000107","article-title":"Sex differences in disease presentation, treatment and clinical outcomes of patients with hepatocellular carcinoma: a single-centere cohort study","volume":"3","author":"MR Ladenheim","year":"2016","journal-title":"BMJ Open Gastro"},{"issue":"40","key":"pone.0262485.ref011","doi-asserted-by":"crossref","first-page":"68131","DOI":"10.18632\/oncotarget.19245","article-title":"Age-specific sex difference in the incidence of hepatocellular carcinoma in the United States.","volume":"8","author":"P Liu","year":"2017","journal-title":"Oncotarget"},{"key":"pone.0262485.ref012","doi-asserted-by":"crossref","first-page":"66","DOI":"10.20517\/2394-5079.2018.87","article-title":"Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease\/steatohepatitis and liver transplantation","volume":"4","author":"EM Wu","year":"2018","journal-title":"Hepatoma Res"},{"key":"pone.0262485.ref013","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1186\/s12885-019-6168-1","article-title":"Female sex is associated with lower risk of bone metastases and favorable prognosis in non-sex-specific cancers","volume":"19","author":"W Ma","year":"2019","journal-title":"BMC Cancer"},{"issue":"11","key":"pone.0262485.ref014","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1016\/j.cgh.2017.05.036","article-title":"Estrogen replacement reduces risk and increases survival times of women with hepatocellular carcinoma","volume":"15","author":"MM Hassan","year":"2017","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"4","key":"pone.0262485.ref015","doi-asserted-by":"crossref","first-page":"e0153863","DOI":"10.1371\/journal.pone.0153863","article-title":"Cytochrome P450 1A2 metabolizes 17\u03b2-estradiol to suppress hepatocellular carcinoma.","volume":"11","author":"J Ren","year":"2016","journal-title":"PLoS ONE."},{"key":"pone.0262485.ref016","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jsbmb.2016.05.023","article-title":"Merlin. the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells","volume":"172","author":"L Cocciadiferro","year":"2017","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"8","key":"pone.0262485.ref017","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.3390\/ijerph17082620","article-title":"Sex hormone-dependent physiology and diseases of liver","volume":"17","author":"P Kur","year":"2020","journal-title":"Int J Environ Res Public Health"},{"issue":"6","key":"pone.0262485.ref018","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.jhep.2009.12.034","article-title":"Cancer gene discovery in hepatocellular carcinoma","volume":"52","author":"L Zender","year":"2010","journal-title":"J Hepatol"},{"issue":"2","key":"pone.0262485.ref019","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/jcmm.12153","article-title":"The role of EGF-EGFR signaling pathway in hepatocellular carcinoma inflammatory microenvironment","volume":"18","author":"P Huang","year":"2014","journal-title":"J Cell Mol Med"},{"issue":"2","key":"pone.0262485.ref020","first-page":"559","article-title":"Differential expression of transforming growth factor alpha, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis","volume":"15","author":"K Jaskiewicz","year":"1995","journal-title":"Anticancer Res"},{"issue":"10","key":"pone.0262485.ref021","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/apm.12431","article-title":"Impact of epidermal growth factor receptor and transforming growth factor-\u03b1 on hepatitis C virus-induced hepatocarcinogenesis","volume":"123","author":"AA Badawy","year":"2015","journal-title":"APMIS"},{"issue":"4","key":"pone.0262485.ref022","doi-asserted-by":"crossref","first-page":"e0151907","DOI":"10.1371\/journal.pone.0151907","article-title":"Phosphorylated heat shock protein 20 (HSPB6) regulates transforming growth factor-\u03b1-induced migration and invasion of hepatocellular carcinoma cells.","volume":"11","author":"R Matsushima-Nishiwaki","year":"2016","journal-title":"PLoS ONE."},{"key":"pone.0262485.ref023","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.bbadis.2017.04.021","article-title":"Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)\/AKT pathway.","volume":"1863","author":"R Matsushima-Nishiwaki","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"pone.0262485.ref024","first-page":"1","article-title":"Olive oil polyphenols suppress the TGF-\u03b1-induced migration of hepatocellular carcinoma cells.","volume":"1","author":"N Yamada","year":"2019","journal-title":"Biomed Rep."},{"key":"pone.0262485.ref025","first-page":"3858","article-title":"Growth of human hepatoma cells lines with differentiated functions in chemically defined medium","volume":"42","author":"H Nakabayashi","year":"1982","journal-title":"Cancer Res"},{"issue":"26","key":"pone.0262485.ref026","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1021\/jm000170m","article-title":"Pyrazole ligands: structure-affinity\/activity relationships and estrogen receptor-alpha-selective agonists","volume":"43","author":"SR Stauffer","year":"2000","journal-title":"J Med Chem"},{"issue":"10","key":"pone.0262485.ref027","doi-asserted-by":"crossref","first-page":"4241","DOI":"10.1210\/en.2003-0550","article-title":"Evaluation of an estrogen receptor-\u03b2 agonist in animal models of human disease","volume":"144","author":"HA Harris","year":"2003","journal-title":"Endocrinology"},{"issue":"24","key":"pone.0262485.ref028","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1021\/jm010254a","article-title":"Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues","volume":"44","author":"MJ Meyers","year":"2001","journal-title":"J Med Chem"},{"issue":"24","key":"pone.0262485.ref029","doi-asserted-by":"crossref","first-page":"5872","DOI":"10.1021\/jm049631k","article-title":"Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor beta antagonist activity","volume":"47","author":"DR Compton","year":"2004","journal-title":"J Med Chem"},{"issue":"6","key":"pone.0262485.ref030","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S1357-2725(99)00015-1","article-title":"EGF receptor.","volume":"31","author":"A. Wells","year":"1999","journal-title":"Int J Biochem Cell Biol"},{"key":"pone.0262485.ref031","doi-asserted-by":"crossref","first-page":"7273","DOI":"10.1074\/jbc.271.13.7273","article-title":"Mechanistic studies on the inactivation of the proteasome by lactacystin: a central role for clasto-lactacystin beta-lactone","volume":"271","author":"LR Dick","year":"1996","journal-title":"J Biol Chem"},{"key":"pone.0262485.ref032","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1093\/carcin\/bgi002","article-title":"Significance of the Rac signaling pathway in HCC cell motility: implications for a new therapeutic target","volume":"26","author":"TK Lee","year":"2005","journal-title":"Carcinogenesis"},{"key":"pone.0262485.ref033","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cellsig.2011.08.011","article-title":"Rac signaling in breast cancer: A tale of GRFs and GAPs","volume":"24","author":"E Wertheimer","year":"2012","journal-title":"Cell Signal"},{"key":"pone.0262485.ref034","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1002\/art.37922","article-title":"Rac1 is required for matrix metalloprotease 13 production by chondrocytes in response to fibronectin fragments","volume":"65","author":"DL Long","year":"2013","journal-title":"Arthritis Rheum"},{"key":"pone.0262485.ref035","doi-asserted-by":"crossref","first-page":"7618","DOI":"10.1073\/pnas.0307512101","article-title":"Rational design and characterization of a Rac GTPase-specific small molecule inhibitor","volume":"101","author":"Y Gao","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0262485.ref036","doi-asserted-by":"crossref","first-page":"544","DOI":"10.3389\/fendo.2020.00544","article-title":"Expression and role of the G protein-coupled estrogen receptor (GPR30\/GPER) in the development and immune response in female reproductive cancers.","volume":"11","author":"CD Hern\u00e1ndez-Silva","year":"2020","journal-title":"Front Endocinol (Lausanne)."},{"key":"pone.0262485.ref037","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nchembio775","article-title":"Virtual and biomolecular screening converge on a selective agonist for GPR30","volume":"2","author":"CG Bologa","year":"2006","journal-title":"Nat Chem Biol"},{"key":"pone.0262485.ref038","doi-asserted-by":"crossref","first-page":"e0145212","DOI":"10.1371\/journal.pone.0145212","article-title":"A new signaling pathway for HCV inhibition by estrogen: GPR30 activation leads to cleavage of occluding by MMP-9.","volume":"11","author":"L Ulitzky","year":"2016","journal-title":"PLoS ONE."},{"key":"pone.0262485.ref039","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1111\/cas.13940","article-title":"Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6\/glycoprotein 130\/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma","volume":"110","author":"H Ma","year":"2019","journal-title":"Cancer Sci"},{"key":"pone.0262485.ref040","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jsbmb.2013.12.011","article-title":"Use of SERMs for treatment in postmenopausal women","volume":"142","author":"JV Pinkerton","year":"2014","journal-title":"J Steroid Biochem Mol Biol"},{"key":"pone.0262485.ref041","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1749-6632.2002.tb04092.x","article-title":"Hepatoccelular carcinoma Roles of estrogen receptors in the liver","volume":"963","author":"E Villa","year":"2002","journal-title":"Ann NY Acad Sci"},{"key":"pone.0262485.ref042","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1196\/annals.1386.007","article-title":"Hormonal treatment of human hepatocellular carcinoma","volume":"1089","author":"M Di Maio","year":"2006","journal-title":"Ann NY Acad Sci"},{"key":"pone.0262485.ref043","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1194\/jlr.M085191","article-title":"Sphingosine kinase 1 activation by estrogen receptor \u03b136 contributes to tamoxifen resistance in breast cancer","volume":"59","author":"MA Maczis","year":"2018","journal-title":"J Lipid Res"},{"key":"pone.0262485.ref044","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.addr.2010.08.001","article-title":"Selectively targeting estrogen receptors for cancer treatment","volume":"62","author":"EK Shanle","year":"2010","journal-title":"Adv Drug Deliv Rev"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262485","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T18:24:31Z","timestamp":1641839071000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262485"}},"subtitle":[],"editor":[{"given":"Salvatore V.","family":"Pizzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,10]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262485","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,10]]}}}