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However, whether HBV integrated sequences determine genotype pathogenicity and how to block their function during HCC progression remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An in vitro HBV-infected PHH model and liver cancer cell lines were established to confirm the pathogenic potential of HBV-SITEs. The roles of HBV-SITE-1 in HCC development were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of RNA-seq and ChIP-seq.\u00a0Animal models were also used to evaluate the therapeutic effect of HBV-miR-2 inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified nine fragments of\n                      <jats:bold>HBV<\/jats:bold>\n                      <jats:bold>\n                        <jats:underline>S<\/jats:underline>\n                      <\/jats:bold>\n                      equences\n                      <jats:bold>\n                        <jats:underline>I<\/jats:underline>\n                      <\/jats:bold>\n                      ntegrated\n                      <jats:bold>\n                        <jats:underline>T<\/jats:underline>\n                      <\/jats:bold>\n                      o\n                      <jats:bold>\n                        <jats:underline>E<\/jats:underline>\n                      <\/jats:bold>\n                      nhancer, termed as \u201cHBV-SITEs\u201d. Particularly, a single nucleotide variation (T\u2009&gt;\u2009G) was embedded at seed sequence of HBV-miR-2 in the highest integrated HBV-SITE-1 between genotypes B and H. Unexpectedly, B-HBV-SITE-1, not H-HBV-SITE-1, could abnormally activate oncogenic genes including\n                      <jats:italic>TERT<\/jats:italic>\n                      and accelerate HCC cell proliferation and migration. Meanwhile, HBV-miR-2 was gradually increased in HBV-infected cells and patient plasma with different HCC stages. Importantly, 227 genes upregulated by HBV, were also activated by HBV-miR-2 through triggering HBV-SITE-1 enhancer. Conversely, enhancer activities were particularly decreased by HBV-miR-2 inhibitors, and further downregulated activated oncogenic genes. Finally, HCC growth was dramatically restrained and HBV-induced transcripts were systematically reduced via injection of HBV-miR-2 inhibitors in animal models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HBV-SITEs were identified as novel oncogenic elements for HCC, which provides an insightful perspective for the other cancers caused by oncogenic DNA viruses. We demonstrated that the integrated HBV sequence itself acted as oncogenic enhancers and nucleotide variations of HBV genotypes account for particular pathogenic progression, supporting that the viral nucleotide sequences are vital pathogenic substances beyond viral proteins. And modulation of their enhancer activities could be clinically achievable strategy for blocking DNA viruses-related cancer progression in the future.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03413-8","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T04:31:17Z","timestamp":1747888277000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["HBV sequence integrated to enhancer acting as oncogenic driver epigenetically promotes hepatocellular carcinoma development"],"prefix":"10.1186","volume":"44","author":[{"given":"Lu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlong","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunyan","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaicheng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanrui","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoming","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"3413_CR1","doi-asserted-by":"crossref","unstructured":"Panduro A, Roman S, Laguna-Meraz S, Jose-Abrego A, Hepatitis B, Virus Genotype H. 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Nat Rev Gastroenterol Hepatol. 2023;20(4):203\u201322.","journal-title":"Nat Rev Gastroenterol Hepatol"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03413-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-025-03413-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03413-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T06:03:42Z","timestamp":1747893822000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-025-03413-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":103,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3413"],"URL":"https:\/\/doi.org\/10.1186\/s13046-025-03413-8","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]},"assertion":[{"value":"8 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were approved by the Fudan Committee on Animal Care and in compliance with ethical guidelines. The use of human serums was obtained with the approval of the Committee of Zhongshan Hospital of Fudan University. All patients provided informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors agreed on the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Shuai Yang is the R&D Director for Shanghai Epicurer Biotechnology Co., Ltd. Wenqiang Yu serves on the Scientific Advisory Board of Epicurer. Epicurer have approved pending patents related to this work. All the other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"155"}}