{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:21:29Z","timestamp":1791836489298,"version":"4.3.4"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>HBV\u2010pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV\u2010pgRNA to HCC remain open for study.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Double\u2010center cohorts of serum samples with undetectable serum HBV\u2010DNA (below the lower limit of detection) were obtained from long\u2010term NA\u2010treated (\u226548\u00a0weeks) HBV\u2010related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. Our findings revealed that for patients who underwent long\u2010term NA therapy with undetectable serum HBV\u2010DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up\u2010regulate the expression of insulin\u2010like growth factor 2 mRNA\u2010binding protein 3 (IGF2BP3), a well\u2010proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)\u2010\u03b1\u20102a could degrade the stability of pgRNA through increasing its N6\u2010methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long\u2010term NA therapy with undetectable serum HBV\u2010DNA; and the pgRNA\u2010IGF2BP3 axis plays an important role in the development of HBV\u2010related HCC. Moreover, IFN\u2010\u03b1\u20102a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV\u2010related HCC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, our studies reveal a significance and mechanism of HBV\u2010pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV\u2010related HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31850","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T03:32:07Z","timestamp":1617766327000},"page":"1480-1495","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":67,"title":["HBV\/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV\u2010Related HCC Through Reciprocal Regulation With Insulin\u2010Like Growth Factor 2 mRNA\u2010Binding Protein 3"],"prefix":"10.1097","volume":"74","author":[{"given":"Wen\u2010bin","family":"Ding","sequence":"first","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2010chao","family":"Wang","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology 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(EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da\u2010peng","family":"Sun","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yang","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology 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Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH),Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Yang","sequence":"additional","affiliation":[{"name":"The Department of Medical Genetics,Second Military Medical University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng\u2010xian","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"},{"name":"Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU),Ministry of Education,Shanghai,China"},{"name":"Shanghai Key Laboratory of Hepatobiliary Tumor Biology 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