{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T16:09:21Z","timestamp":1775923761882,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T00:00:00Z","timestamp":1658016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Agency for Medical Research and Development","award":["#JP20fk0210054"],"award-info":[{"award-number":["#JP20fk0210054"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.<\/jats:p>","DOI":"10.3390\/ijms23147878","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"7878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The RNA-Binding Protein ELAVL1 Regulates Hepatitis B Virus Replication and Growth of Hepatocellular Carcinoma Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Hiroaki","family":"Kanzaki","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7179-0765","authenticated-orcid":false,"given":"Tetsuhiro","family":"Chiba","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Ao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoyasu","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Muroyama","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shingo","family":"Nakamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1654-5385","authenticated-orcid":false,"given":"Tatsuo","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoh","family":"Zen","sequence":"additional","affiliation":[{"name":"Institute of Liver Studies, King\u2019s College Hospital, London SE5 9RS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai","family":"Kotani","sequence":"additional","affiliation":[{"name":"Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-1974","authenticated-orcid":false,"given":"Kazuma","family":"Sekiba","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoyuki","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Ohtsuka","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5812-2818","authenticated-orcid":false,"given":"Naoya","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1001\/jama.2018.3795","article-title":"Chronic hepatitis B infection: A Review","volume":"319","author":"Tang","year":"2018","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/S1473-3099(16)30325-5","article-title":"Estimating the burden of disease attributable to injecting drug use as a risk factor for HIV, hepatitis C, and hepatitis B: Findings from the Global Burden of Disease Study 2013","volume":"16","author":"Degenhardt","year":"2016","journal-title":"Lancet Infect Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jhep.2009.05.022","article-title":"Control of cccDNA function in hepatitis B virus infection","volume":"51","author":"Levrero","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/jmbi.2000.4481","article-title":"Structural organization of the hepatitis B virus minichromosome","volume":"307","author":"Bock","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1128\/MMBR.64.1.51-68.2000","article-title":"Hepatitis B virus biology","volume":"64","author":"Seeger","year":"2000","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23237","DOI":"10.1038\/srep23237","article-title":"Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7","volume":"6","author":"Takata","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.jhep.2015.09.013","article-title":"Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122","volume":"64","author":"Liang","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.jhep.2017.05.025","article-title":"Alternative splicing of hepatitis B virus: A novel virus\/host interaction altering liver immunity","volume":"67","author":"Duriez","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1056\/NEJMoa0802878","article-title":"Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B","volume":"359","author":"Marcellin","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1056\/NEJMoa021812","article-title":"Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B","volume":"348","author":"Hadziyannis","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20953","DOI":"10.18632\/oncotarget.25104","article-title":"DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels","volume":"9","author":"Sekiba","year":"2018","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1002\/cbic.200400219","article-title":"mRNA openers and closers: Modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure","volume":"5","author":"Meisner","year":"2004","journal-title":"ChemBioChem"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1056\/NEJMoa033364","article-title":"Lamivudine for patients with chronic hepatitis B and advanced liver disease","volume":"351","author":"Liaw","year":"2004","journal-title":"N. Eng. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/hep.26180","article-title":"Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection","volume":"58","author":"Hosaka","year":"2013","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104824","DOI":"10.1016\/j.antiviral.2020.104824","article-title":"Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential","volume":"180","author":"Xia","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jhep.2016.03.013","article-title":"HBcrAg predicts hepatocellular carcinoma development: An analysis using time-dependent receiver operating characteristics","volume":"65","author":"Tada","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/liv.14364","article-title":"Can we cure hepatitis B virus with novel direct-acting antivirals?","volume":"40","author":"Martinez","year":"2020","journal-title":"Liver Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jhep.2021.05.013","article-title":"Covalently closed circular DNA: The ultimate therapeutic target for curing HBV infections","volume":"75","author":"Martinez","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1128\/mr.59.3.423-450.1995","article-title":"mRNA stability in mammalian cells","volume":"59","author":"Ross","year":"1995","journal-title":"Microbiol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1128\/MCB.15.4.2219","article-title":"The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation","volume":"15","author":"Zubiaga","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10015","DOI":"10.3390\/ijms140510015","article-title":"Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis","volume":"14","author":"Wang","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00018-011-0810-7","article-title":"The complex world of post-transcriptional mechanisms: Is their deregulation a common link for diseases? Focus on ELAV-like RNA-binding proteins","volume":"69","author":"Pascale","year":"2012","journal-title":"Cell Mol. Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1093\/emboj\/19.10.2340","article-title":"HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation","volume":"19","author":"Wang","year":"2000","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5889","DOI":"10.1128\/MCB.21.17.5889-5898.2001","article-title":"Loss of HuR is linked to reduced expression of proliferative genes during replicative senescence","volume":"21","author":"Wang","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4161\/rna.2.1.1552","article-title":"HuR: Post-transcriptional paths to malignancy","volume":"2","author":"Lal","year":"2005","journal-title":"RNA Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s12032-014-0161-y","article-title":"Clinical significance of HuR expression in human malignancy","volume":"31","author":"Giaginis","year":"2014","journal-title":"Med. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1479-828X.2008.00937.x","article-title":"HuR expression in the nucleus correlates with high histological grade and poor disease-free survival in ovarian cancer","volume":"49","author":"Yi","year":"2009","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1245\/s10434-008-0209-3","article-title":"Tissue microarray analysis of 560 patients with colorectal adenocarcinoma. high expression of HuR predicts poor survival","volume":"16","author":"Yoo","year":"2009","journal-title":"Ann. Surg. Oncol."},{"key":"ref_29","first-page":"182","article-title":"Hepatitis B virus X protein accelerates the development of hepatoma","volume":"11","author":"Zhang","year":"2014","journal-title":"Cancer Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.coviro.2018.01.007","article-title":"Role of HBx in hepatitis B virus persistence and its therapeutic implications","volume":"30","author":"Slagle","year":"2018","journal-title":"Curr. Opin. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1158\/0008-5472.CAN-04-3765","article-title":"Cytoplasmic HuR Expression Is a Prognostic Factor in Invasive Ductal Breast Carcinoma","volume":"65","author":"Heinonen","year":"2005","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Miyata, Y., Watanabe, S., Sagara, Y., Nitsunari, K., Natsuo, T., Ohba, K., and Sakai, H. (2013). High expression of HuR in cytoplasm, but not nuclei, is associated with malignant aggressiveness and prognosis in bladder cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059095"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Papatheofani, V., Levidou, G., Sarantis, P., Koustas, E., Karamouzis, M.V., Pergaris, A., Kouraklis, G., and Theocharis, S. (2021). HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020119"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kakizaki, M., Yamamoto, Y., Yabuta, S., Kurosaki, N., Kagawa, T., and Kotani, A. (2018). The immunological function of extracellular vesicles in hepatitis B virus-infected hepatocytes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205886"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1128\/AAC.41.8.1715","article-title":"Inducible expression of human hepatitis B virus (HBV) in stably transfected hepatoblastoma cells: A novel system for screening potential inhibitors of HBV replication","volume":"41","author":"Ladner","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.jcmgh.2018.10.010","article-title":"Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx\u2013DDB1 Interaction","volume":"7","author":"Sekiba","year":"2019","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.3892\/ol.2020.11757","article-title":"Interferon-\u03b3 induced PD-L1 expression and soluble PD-L1 production in gastric cancer","volume":"20","author":"Imai","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7742","DOI":"10.1158\/0008-5472.CAN-07-5882","article-title":"The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma","volume":"68","author":"Chiba","year":"2008","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:28Z","timestamp":1760140348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,17]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147878"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147878","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,17]]}}}