{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T06:51:25Z","timestamp":1769151085177,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG8J1041"],"award-info":[{"award-number":["CMRPG8J1041"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CORPG8K0021"],"award-info":[{"award-number":["CORPG8K0021"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is the most common cause of primary liver cancer deaths worldwide. The major risk factors for liver cancer development are cirrhosis, hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and chronic alcohol abuse. HCC displays heterogeneity in terms of biology, etiology, and epidemiology. In Southeast Asia and Africa, chronic HBV infection is a major risk factor for HCC, whereas chronic HCV infection is a risk factor for HCC in western countries and Japan. Environmental and genetic conditions also play a role in the regional and temporal variations in the incidence of HCC. In this study, we used the ESTIMATE (ESTIMATE, Estimation of stromal and immune cells in malignant tumor tissues using expression data) algorithm and the CIBERSOFT tool to analyze gene expression profiles and infiltrating immune cells in HCC between Asian and non-Asian patients. The results showed that stromal and immune scores were dependent on overall survival (OS) in non-Asian patients but not in Asian patients. Kaplan\u2013Meier survival analysis revealed four differentially expressed genes (DEGs) that were significantly associated with OS in non-Asian patients only. CIBERSORT (CIBERSORT, Cell type identification by estimating relative subsets of known RNA transcripts) analysis indicated that the composition of infiltrating immune cells was significantly different between Asian and non-Asian patients. By parsing the subclasses of HCC, the ability to predict prognosis and guide therapeutic targets for potentially actionable HCC may be improved.<\/jats:p>","DOI":"10.3390\/genes12081274","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:44:45Z","timestamp":1629449085000},"page":"1274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Disparity of Hepatocellular Carcinoma in Tumor Microenvironment-Related Genes and Infiltrating Immune Cells between Asian and Non-Asian Populations"],"prefix":"10.3390","volume":"12","author":[{"given":"Lien-Hung","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-Min","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8192-0129","authenticated-orcid":false,"given":"Chun-Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueh-Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-6921","authenticated-orcid":false,"given":"Shao-Chun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng-Chen","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Hua","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis","volume":"152","author":"Sia","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","author":"Llovet","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187204","DOI":"10.1155\/2013\/187204","article-title":"The inflammatory microenvironment in hepatocellular carcinoma: A pivotal role for tumor-associated macrophages","volume":"2013","author":"Capece","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1207\/s15327914nc4801_3","article-title":"Population-attributable risk of dietary aflatoxins and hepatitis B virus infection with respect to hepatocellular carcinoma","volume":"48","author":"Omer","year":"2004","journal-title":"Nutr. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/ijc.26165","article-title":"Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: A systematic review and meta-analysis of cohort studies","volume":"130","author":"Wang","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1053\/j.gastro.2015.05.061","article-title":"Genetic Landscape and Biomarkers of Hepatocellular Carcinoma","volume":"149","author":"Villanueva","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ctrv.2011.06.010","article-title":"Role of the microenvironment in hepatocellular carcinoma development and progression","volume":"38","author":"Wu","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.semcancer.2010.10.007","article-title":"The tumor microenvironment in hepatocellular carcinoma: Current status and therapeutic targets","volume":"21","author":"Yang","year":"2011","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","first-page":"82","article-title":"Roles of Tumor Microenvironment in Hepatocelluar Carcinoma","volume":"11","author":"Seo","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.3390\/cancers7040902","article-title":"Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth","volume":"7","author":"Shiga","year":"2015","journal-title":"Cancers"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Birgani, M.T., and Carloni, V. (2017). Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020405"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrc1877","article-title":"Fibroblasts in cancer","volume":"6","author":"Kalluri","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.bpg.2011.02.005","article-title":"Mechanisms of hepatic fibrogenesis","volume":"25","author":"Lee","year":"2011","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/labinvest.2013.139","article-title":"Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model","volume":"94","author":"Zhao","year":"2014","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8866","DOI":"10.18632\/oncotarget.6839","article-title":"Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2","volume":"7","author":"Xu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"Grivennikov","year":"2010","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1189\/jlb.0609385","article-title":"Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation","volume":"86","author":"Solinas","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1158\/0008-5472.CAN-05-4005","article-title":"Distinct role of macrophages in different tumor microenvironments","volume":"66","author":"Lewis","year":"2006","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1053\/j.gastro.2007.03.102","article-title":"Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients","volume":"132","author":"Fu","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e19561","DOI":"10.1097\/MD.0000000000019561","article-title":"Exploring immune-related genes with prognostic value in microenvironment of breast cancer from TCGA database","volume":"99","author":"Yang","year":"2020","journal-title":"Medicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6999","DOI":"10.18632\/aging.102233","article-title":"Prognostic value and immune infiltration of novel signatures in clear cell renal cell carcinoma microenvironment","volume":"11","author":"Xu","year":"2019","journal-title":"Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4980","DOI":"10.1002\/cam4.2801","article-title":"Stromal score as a prognostic factor in primary gastric cancer and close association with tumor immune microenvironment","volume":"9","author":"Mao","year":"2020","journal-title":"Cancer Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"541330","DOI":"10.3389\/fonc.2020.541330","article-title":"Immune-Stromal Score Signature: Novel Prognostic Tool of the Tumor Microenvironment in Lung Adenocarcinoma","volume":"10","author":"Qi","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5479","DOI":"10.18632\/aging.102971","article-title":"Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma","volume":"12","author":"Ge","year":"2020","journal-title":"Aging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1002\/ijc.25516","article-title":"Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008","volume":"127","author":"Ferlay","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/hep.31288","article-title":"Epidemiology of Hepatocellular Carcinoma","volume":"73","author":"McGlynn","year":"2021","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular Carcinoma","volume":"380","author":"Villanueva","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1002\/cncr.30237","article-title":"Comparison of hepatocellular carcinoma in Eastern versus Western populations","volume":"122","author":"Choo","year":"2016","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2147\/JHC.S61146","article-title":"Hepatocellular carcinoma: A review","volume":"3","author":"Balogh","year":"2016","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1002\/hep.27222","article-title":"Epidemiology of hepatocellular carcinoma in the United States: Where are we? Where do we go?","volume":"60","author":"Kanwal","year":"2014","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11894-019-0681-x","article-title":"The Epidemiology of Hepatocellular Carcinoma in the USA","volume":"21","author":"Kim","year":"2019","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7251","DOI":"10.7314\/APJCP.2013.14.12.7251","article-title":"Attributable causes of liver cancer mortality and incidence in china","volume":"14","author":"Fan","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/j.1440-1746.2007.04908.x","article-title":"Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: A case-control study of 213 hepatocellular carcinoma patients from India","volume":"22","author":"Kumar","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1016\/j.jceh.2014.05.013","article-title":"Epidemiology of hepatocellular carcinoma in India","volume":"4","author":"Acharya","year":"2014","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1089\/dna.2020.5512","article-title":"A Five-Gene Signature Based on Stromal\/Immune Scores in the Tumor Microenvironment and Its Clinical Implications for Liver Cancer","volume":"39","author":"Liu","year":"2020","journal-title":"DNA Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1093\/bioinformatics\/bts624","article-title":"Distinction immune genes of hepatitis-induced heptatocellular carcinoma","volume":"28","author":"Hu","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/cncr.20842","article-title":"Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association","volume":"103","author":"Nieters","year":"2005","journal-title":"Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1093\/carcin\/bgn286","article-title":"Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA","volume":"30","author":"Ognjanovic","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"262385","DOI":"10.1155\/2014\/262385","article-title":"Serum SALL4 is a novel prognosis biomarker with tumor recurrence and poor survival of patients in hepatocellular carcinoma","volume":"2014","author":"Han","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1097\/PAS.0000000000000218","article-title":"SALL4 immunoreactivity predicts prognosis in Western hepatocellular carcinoma patients but is a rare event: A study of 236 cases","volume":"38","author":"Liu","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"601710","DOI":"10.3389\/fonc.2020.601710","article-title":"Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease","volume":"10","author":"Suresh","year":"2020","journal-title":"Front. Oncol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1274\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:09Z","timestamp":1760165289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["genes12081274"],"URL":"https:\/\/doi.org\/10.3390\/genes12081274","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,20]]}}}