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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    We investigated the role of tumor microenvironment (TME) in evolution of liver cirrhosis to hepatocellular carcinoma (HCC). Nonmalignant hepatic tissues, including chronic hepatitis and cirrhosis, retained expression of liver specific\n                    <jats:italic toggle=\"yes\">miR-122<\/jats:italic>\n                    and hepatocyte nuclear factor 4 (HNF-4) transcription factor and exhibited an immune surveillance program characterized by Inducible T cell Costimulatory Ligand (ICOSL) and NF-\u03baB expression, low Suppressor of Cytokine Signaling 1 (SOCS1) levels, and abundant cytotoxic T cell infiltration. In contrast, progression to HCC was associated with loss of cytotoxic T cells, loss of ICOSL, PDL1, HNF-4, SMAD7, and NF-\u03baB expression, and marked upregulation of YAP1 oncogene. TGF-\u03b2 overexpression was induced by SMAD7 loss, mediated by\n                    <jats:italic toggle=\"yes\">miR-21<\/jats:italic>\n                    upregulation. Loss of HNF4, was associated with reduced miR-122 expression and subsequent upregulation of its target, SOCS1. Chronic inflammation, driven by\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    , created an immune permissive environment that facilitated\n                    <jats:italic toggle=\"yes\">miR-21 induction<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">miR-122 loss<\/jats:italic>\n                    . In addition,\n                    <jats:italic toggle=\"yes\">miR-21<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    contributed to malignant transformation through suppression of numerous tumor suppressor genes and enhanced YAP1 expression, a potent hepatocyte oncogene. These findings were recapitulated in orthotopic HCC mouse models, which demonstrated loss of ICOSL, PDL1, and HNF4 expression, minimal cytotoxic T cell infiltration, and increased of SOCS1, YAP1, and TGF-\u03b2 expression. It is concluded that the transition from cirrhosis to HCC is associated by coordinated immunosuppression and oncogenic signaling driven by\n                    <jats:italic toggle=\"yes\">miR-21<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    , together with the loss of\n                    <jats:italic toggle=\"yes\">miR-122<\/jats:italic>\n                    . Targeting\n                    <jats:italic toggle=\"yes\">miR-155<\/jats:italic>\n                    may therefore represent a preventive strategy for HCC development in patients with chronic viral hepatitis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2618249123","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:02:56Z","timestamp":1790622176000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["MicroRNA-driven regulation of immunosuppressive microenvironment in hepatocellular carcinoma"],"prefix":"10.1073","volume":"123","author":[{"given":"Gerard J.","family":"Nuovo","sequence":"first","affiliation":[{"name":"GNOME Diagnostics","place":["Powell"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Heineman","sequence":"additional","affiliation":[{"name":"Oncolytics Biotech Inc.","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmerina","family":"Tili","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/028t46f04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center and The Ohio State University College of Medicine, Wexner Medical Center","place":["Columbus"]},{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesiology, Wexner Medical Center, The Ohio State University College of Medicine","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-1457","authenticated-orcid":false,"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/028t46f04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center and The Ohio State University College of Medicine, Wexner Medical Center","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2408649121"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2422615122"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02273-0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602266103"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmr.2025.100088"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00752-08"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2509425122"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2536375123"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02075-w"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01308-4"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-01024-w"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13776"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.01.3441"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2020-0162"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31046-2"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30156-X"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i14.1653"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.028"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327059"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1053\/hupa.2002.32211"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.89568"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1580500"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00533.x"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-2123"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26257"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25849"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2023.07.012"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605958"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026971"},{"key":"e_1_3_4_30_2","first-page":"263","article-title":"Regulation of TGF beta signaling by SMAD7","volume":"41","author":"Yan X.","year":"2009","unstructured":"X. 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