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Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways. Virus-host regulatory pathways, interactions between proteins, gene expression, transport, and stability regulation, were reconstructed using the ANDSystem. Gene expression regulation was statistically significant. Gene network analysis identified four out of 70 HCC marker genes whose expression regulation by viral proteins may be associated with HCC: <jats:italic>DNA-binding protein inhibitor ID \u2013 1 (ID1)<\/jats:italic>, <jats:italic>flap endonuclease 1 (FEN1)<\/jats:italic>, <jats:italic>cyclin-dependent kinase inhibitor 2A (CDKN2A)<\/jats:italic>, and <jats:italic>telomerase reverse transcriptase (TERT)<\/jats:italic>. It suggested the following viral protein effects in HCV\/human protein heterocomplexes: HCV NS3(p70) protein activates human STAT3 and NOTC1; NS2-3(p23), NS5B(p68), NS1(E2), and core(p21) activate SETD2; NS5A inhibits SMYD3; and NS3 inhibits CCN2. Interestingly, NS3 and E1(gp32) activate c-Jun when it positively regulates <jats:italic>CDKN2A<\/jats:italic> and inhibit it when it represses <jats:italic>TERT<\/jats:italic>. The discovered regulatory mechanisms might be key areas of focus for creating medications and preventative therapies to decrease the likelihood of HCC development during HCV infection.<\/jats:p>","DOI":"10.1515\/jib-2023-0013","type":"journal-article","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T09:21:30Z","timestamp":1700299290000},"source":"Crossref","is-referenced-by-count":6,"title":["Reconstruction of the regulatory hypermethylation network controlling hepatocellular carcinoma development during hepatitis C viral infection"],"prefix":"10.1515","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2158-3252","authenticated-orcid":false,"given":"Evgeniya A.","family":"Antropova","sequence":"first","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"}]},{"given":"Tamara M.","family":"Khlebodarova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-8341","authenticated-orcid":false,"given":"Pavel S.","family":"Demenkov","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"given":"Anastasiia R.","family":"Volianskaia","sequence":"additional","affiliation":[{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-5168","authenticated-orcid":false,"given":"Artur S.","family":"Venzel","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-8117","authenticated-orcid":false,"given":"Nikita V.","family":"Ivanisenko","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"}]},{"given":"Alexandr D.","family":"Gavrilenko","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0005-9155","authenticated-orcid":false,"given":"Timofey V.","family":"Ivanisenko","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"}]},{"given":"Anna V.","family":"Adamovskaya","sequence":"additional","affiliation":[{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"given":"Polina M.","family":"Revva","sequence":"additional","affiliation":[{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6800-8787","authenticated-orcid":false,"given":"Nikolay A.","family":"Kolchanov","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-309X","authenticated-orcid":false,"given":"Inna N.","family":"Lavrik","sequence":"additional","affiliation":[{"name":"Translational Inflammation Research, Medical Faculty , Otto von Guericke University Magdeburg , 39106 Magdeburg , Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-4631","authenticated-orcid":false,"given":"Vladimir A.","family":"Ivanisenko","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of RAS , Novosibirsk , Russia"},{"name":"Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia"},{"name":"Novosibirsk State University , Novosibirsk , Russia"}]}],"member":"374","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"2024071808435869217_j_jib-2023-0013_ref_001","doi-asserted-by":"crossref","unstructured":"Ahmad, FB, Cisewski, JA, Anderson, RN. 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