{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T13:03:22Z","timestamp":1777035802409,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) remains a major challenge to clinicians due to its unacceptably high mortality and morbidity. The etiology of HCC is multi-faceted, including viral infection, alcoholism and non-alcoholic fatty liver disease. Dysregulated host immunity contributes to tumorigenesis among these susceptible individuals with pre-existing condition(s). IL-32 and IL-34 are key cytokines driving the development of chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, as well as chronic liver diseases. IL-32 and IL-34 play an important role augmenting the development of HCC, due to their direct influence over host inflammation, however, new roles for these cytokines in HCC are emerging. Here we comprehensively review the latest research for IL-32 and IL-34 in HCC, identifying a subset of potential therapeutic targets for use in precision medicine.<\/jats:p>","DOI":"10.3389\/fmed.2022.1051113","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T05:20:30Z","timestamp":1668144030000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["IL-32 and IL-34 in hepatocellular carcinoma"],"prefix":"10.3389","volume":"9","author":[{"given":"Yang","family":"Si","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shisan","family":"Bao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven G.","family":"Wise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular carcinoma","volume":"380","author":"Villanueva","year":"2019","journal-title":"N Engl J Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat Rev Dis Primers."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1055\/s-0038-1676806","article-title":"Inflammation and liver cancer: molecular mechanisms and therapeutic targets","volume":"39","author":"Yang","year":"2019","journal-title":"Semin Liver Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10238-022-00810-7","article-title":"Combination of IL-34 and AFP improves the diagnostic value during the development of HBV related hepatocellular carcinoma","author":"Liu","year":"2022","journal-title":"Clin Exp Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"526","DOI":"10.3390\/medicina55090526","article-title":"Hepatocellular carcinoma: molecular mechanisms and targeted therapies","volume":"55","author":"Alqahtani","year":"2019","journal-title":"Medicina."},{"key":"B7","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/S1074-7613(04)00380-2","article-title":"Interleukin-32: a cytokine and inducer of TNFalpha","volume":"22","author":"Kim","year":"2005","journal-title":"Immunity."},{"key":"B8","doi-asserted-by":"publisher","first-page":"R166","DOI":"10.1186\/ar2074","article-title":"Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases","volume":"8","author":"Shoda","year":"2006","journal-title":"Arthritis Res Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e13012","DOI":"10.1111\/sji.13012","article-title":"The role of interleukin-32 in autoimmunity","volume":"93","author":"de Albuquerque","year":"2021","journal-title":"Scand J Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1002\/hep.27328","article-title":"IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells","volume":"60","author":"Preisser","year":"2014","journal-title":"Hepatology."},{"key":"B11","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.str.2012.02.010","article-title":"Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R","volume":"20","author":"Ma","year":"2012","journal-title":"Structure."},{"key":"B12","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1042\/CS20150176","article-title":"Interleukin 34: a new modulator of human and experimental inflammatory bowel disease","volume":"129","author":"Zwicker","year":"2015","journal-title":"Clin Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s00296-014-3056-5","article-title":"Baseline serum interleukin-34 levels independently predict radiographic progression in patients with rheumatoid arthritis","volume":"35","author":"Chang","year":"2015","journal-title":"Rheumatol Int."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3198","DOI":"10.1172\/JCI81166","article-title":"IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease","volume":"125","author":"Baek","year":"2015","journal-title":"J Clin Invest."},{"key":"B15","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13578-020-00454-8","article-title":"Inverse correlation between interleukin-34 and gastric cancer, a potential biomarker for prognosis","volume":"10","author":"Liu","year":"2020","journal-title":"Cell Biosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/(SICI)1098-2795(199701)46:1<4::AID-MRD2>3.0.CO;2-V","article-title":"Biology and action of colony\u2013stimulating factor-1","volume":"46","author":"Stanley","year":"1997","journal-title":"Mol Reprod Dev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.3748\/wjg.v24.i12.1312","article-title":"Serum interleukin-34 level can be an indicator of liver fibrosis in patients with chronic hepatitis B virus infection","volume":"24","author":"Wang","year":"2018","journal-title":"World J Gastroenterol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","article-title":"Enhancement of antitumor immunity by CTLA-4 blockade","volume":"271","author":"Leach","year":"1996","journal-title":"Science."},{"key":"B19","doi-asserted-by":"publisher","first-page":"940","DOI":"10.3389\/fimmu.2020.00940","article-title":"The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses","volume":"11","author":"Labani-Motlagh","year":"2020","journal-title":"Front Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.copbio.2016.02.007","article-title":"Impact of the physical microenvironment on tumor progression and metastasis","volume":"40","author":"Spill","year":"2016","journal-title":"Curr Opin Biotechnol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nri2785","article-title":"FOXP3+ regulatory T cells in the human immune system","volume":"10","author":"Sakaguchi","year":"2010","journal-title":"Nat Rev Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"583084","DOI":"10.3389\/fimmu.2020.583084","article-title":"Tumor-Associated macrophages in tumor immunity","volume":"11","author":"Pan","year":"2020","journal-title":"Front Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"289","DOI":"10.2217\/imt-2016-0135","article-title":"Tumor-associated macrophages: implications in cancer immunotherapy","volume":"9","author":"Petty","year":"2017","journal-title":"Immunotherapy."},{"key":"B24","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm","volume":"11","author":"Biswas","year":"2010","journal-title":"Nat Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nature12034","article-title":"Macrophage biology in development, homeostasis and disease","volume":"496","author":"Wynn","year":"2013","journal-title":"Nature."},{"key":"B26","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/ijc.29376","article-title":"Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment","volume":"137","author":"S\u00e9galiny","year":"2015","journal-title":"Int J Cancer."},{"key":"B27","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.canlet.2011.12.023","article-title":"Dysregulation of overexpressed IL-32alpha in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-kappaB and Bcl-2","volume":"318","author":"Kang","year":"2012","journal-title":"Cancer Lett."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.3892\/or.2017.6162","article-title":"Overexpression of interleukin-32alpha promotes invasion by modulating VEGF in hepatocellular carcinoma","volume":"39","author":"Zhao","year":"2018","journal-title":"Oncol Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/S0962-8924(98)01273-2","article-title":"The central executioners of apoptosis: caspases or mitochondria?","volume":"8","author":"Green","year":"1998","journal-title":"Trends Cell Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/s41423-022-00905-x","article-title":"Role of pyroptosis in inflammation and cancer","volume":"19","author":"Wei","year":"2022","journal-title":"Cell Mol Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.5483\/BMBRep.2019.52.3.019","article-title":"Interleukin-32: frenemy in cancer?","volume":"52","author":"Han","year":"2019","journal-title":"BMB Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1159\/000524977","article-title":"Combination immunotherapy with Anti-PD-1\/PD-L1 antibody plus anti-VEGF antibody may promote cytotoxic T lymphocyte infiltration in hepatocellular carcinoma, including in the noninflamed subclass","volume":"11","author":"Kudo","year":"2022","journal-title":"Liver Cancer."},{"key":"B33","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s00262-019-02440-7","article-title":"Interleukin-38 in colorectal cancer: a potential role in precision medicine","volume":"69","author":"Chen","year":"2020","journal-title":"Cancer Immunol Immunother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1093\/jnci\/djq444","article-title":"Sex hormones and colorectal cancer: what have we learned so far?","volume":"102","author":"Lin","year":"2010","journal-title":"J Natl Cancer Inst."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1002\/hep4.1396","article-title":"Interleukin-32 contributes to human nonalcoholic fatty liver disease and insulin resistance","volume":"3","author":"Dali-Youcef","year":"2019","journal-title":"Hepatol Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1002\/oby.21001","article-title":"Interleukin-32beta ameliorates metabolic disorder and liver damage in mice fed high-fat diet","volume":"23","author":"Lee","year":"2015","journal-title":"Obesity."},{"key":"B37","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1042\/CS20140576","article-title":"Interleukin-32gamma attenuates ethanol-induced liver injury by the inhibition of cytochrome P450 2E1 expression and inflammatory responses","volume":"128","author":"Lee","year":"2015","journal-title":"Clin Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"46","DOI":"10.21037\/tgh.2019.12.09","article-title":"Preoperative alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC): is this 50-year biomarker still up-to-date?","volume":"5","author":"Muscari","year":"2020","journal-title":"Transl Gastroenterol Hepatol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1053\/j.gastro.2009.10.064","article-title":"A necrotic liver mass","volume":"139","author":"Sweetser","year":"2010","journal-title":"Gastroenterology."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.jhep.2015.02.010","article-title":"Transarterial chemoembolization: modalities, indication, and patient selection","volume":"62","author":"Sieghart","year":"2015","journal-title":"J Hepatol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1111\/hepr.13350","article-title":"High serum interleukin-34 level is a predictor of poor prognosis in patients with non-viral hepatocellular carcinoma","volume":"49","author":"Noda","year":"2019","journal-title":"Hepatol Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/hep.28445","article-title":"miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis","volume":"63","author":"Zhou","year":"2016","journal-title":"Hepatology."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3527","DOI":"10.3748\/wjg.v25.i27.3527","article-title":"Immune suppression in chronic hepatitis B infection associated liver disease: a review","volume":"25","author":"Li","year":"2019","journal-title":"World J Gastroenterol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"158","DOI":"10.5114\/ceh.2018.78119","article-title":"Immunodeficiency caused by cirrhosis","volume":"4","author":"Tuchendler","year":"2018","journal-title":"Clin Exp Hepatol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.4251\/wjgo.v14.i9.1808","article-title":"Clinical implications of interleukins-31, 32, and 33 in gastric cancer","volume":"14","author":"Liu","year":"2022","journal-title":"World J Gastrointest Oncol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut-liver axis in liver disease: pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J Hepatol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1051113\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T05:20:31Z","timestamp":1668144031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1051113\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":46,"alternative-id":["10.3389\/fmed.2022.1051113"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.1051113","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]},"article-number":"1051113"}}