{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T14:29:20Z","timestamp":1777040960027,"version":"3.51.4"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871965"],"award-info":[{"award-number":["81871965"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hepatocellular carcinoma (HCC) originates from the hepatocytes and accounts for 90% of liver cancer. The study intends to identify novel prognostic biomarkers for predicting the prognosis of HCC patients based on TCGA and GSE14520 cohorts. Methods: Differential analysis was employed to obtain the DEGs (Differentially Expressed Genes) of the TCGA-LIHC-TPM cohort. The lasso regression analysis was applied to build the prognosis model through using the TCGA cohort as the training group and the GSE14520 cohort as the testing group. Next, based on the prognosis model, we performed the following analyses: the survival analysis, the independent prognosis analysis, the clinical feature analysis, the mutation analysis, the immune cell infiltration analysis, the tumor microenvironment analysis, and the drug sensitivity analysis. Finally, the survival time of HCC patients was predicted by constructing nomograms. Results: Through the lasso regression analysis, we obtained a prognosis model of ten genes including BIRC5 (baculoviral IAP repeat containing 5), CDK4 (cyclin-dependent kinase 4), DCK (deoxycytidine kinase), HSPA4 (heat shock protein family A member 4), HSP90AA1 (heat shock protein 90 \u03b1 family class A member 1), PSMD2 (Proteasome 26S Subunit Ubiquitin Receptor, Non-ATPase 2), IL1RN (interleukin 1 receptor antagonist), PGF (placental growth factor), SPP1 (secreted phosphoprotein 1), and STC2 (stanniocalcin 2). First, we found that the risk score is an independent prognosis factor and is related to the clinical features of HCC patients, covering AFP (\u03b1-fetoprotein) and stage. Second, we observed that the p53 mutation was the most obvious mutation between the high-risk and low-risk groups. Third, we also discovered that the risk score is related to some immune cells, covering B cells, T cells, dendritic, macrophages, neutrophils, etc. Fourth, the high-risk group possesses a lower TIDE score, a higher expression of immune checkpoints, and higher ESTIMATE score. Finally, nomograms include the clinical features and risk signatures, displaying the clinical utility of the signature in the survival prediction of HCC patients. Conclusions: Through the comprehensive analysis, we constructed an immune-related prognosis model to predict the survival of HCC patients. In addition to predicting the survival time of HCC patients, this model significantly correlates with the tumor microenvironment. Furthermore, we concluded that these ten immune-related genes (BIRC5, CDK4, DCK, HSPA4, HSP90AA1, PSMD2, IL1RN, PGF, SPP1, and STC2) serve as novel targets for antitumor immunity. Therefore, this study plays a significant role in exploring the clinical application of immune-related genes.<\/jats:p>","DOI":"10.3390\/genes13101834","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T22:18:13Z","timestamp":1665526693000},"page":"1834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Identification and Analysis of Immune-Related Gene Signature in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-3844","authenticated-orcid":false,"given":"Bingbing","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan 430060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan 430060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunxun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan 430060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan 430060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan 430060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in Advanced Hepatocellular Carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1002\/hep.25832","article-title":"Resection of hepatocellular cancer \u22642 cm: Results from two Western centers","volume":"57","author":"Roayaie","year":"2012","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cabibbo, G., Maida, M.F., Genco, C., Alessi, N., Peralta, M., Butera, G., Galia, M., Brancatelli, G., Genova, C., and Raineri, M. (2013). Survival of Patients with Hepatocellular Carcinoma (HCC) Treated by Percutaneous Radio-Frequency Ablation (RFA) Is Affected by Complete Radiological Response. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070016"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41571-019-0203-7","article-title":"Navigating metabolic pathways to enhance antitumour immunity and immunotherapy","volume":"16","author":"Li","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The tumor microenvironment innately modulates cancer progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","article-title":"The tumor microenvironment","volume":"30","author":"Anderson","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kole, C., Charalampakis, N., Tsakatikas, S., Vailas, M., Moris, D., Gkotsis, E., Kykalos, S., Karamouzis, M.V., and Schizas, D. (2020). Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers, 12.","DOI":"10.3390\/cancers12102859"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/hep.31412","article-title":"Intratumoral \u03b3\u03b4 T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4\/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma","volume":"73","author":"Zhao","year":"2021","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s13059-016-1092-z","article-title":"Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures","volume":"17","author":"Gejman","year":"2016","journal-title":"Genome Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling Tumor Infiltrating Immune Cells with CIBERSORT","volume":"1711","author":"Chen","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13073-019-0638-6","article-title":"Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data","volume":"11","author":"Finotello","year":"2019","journal-title":"Genome Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: Digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e26476","DOI":"10.7554\/eLife.26476","article-title":"Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data","volume":"6","author":"Racle","year":"2017","journal-title":"eLife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cmpb.2017.10.023","article-title":"R package to estimate intracluster correlation coefficient with confidence interval for binary data","volume":"155","author":"Chakraborty","year":"2017","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1186\/s13046-019-1362-1","article-title":"Cancer therapeutics using survivin BIRC5 as a target: What can we do after over two decades of study?","volume":"38","author":"Li","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1080\/15548627.2019.1671643","article-title":"BIRC5\/Survivin is a novel ATG12\u2013ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells","volume":"16","author":"Lin","year":"2019","journal-title":"Autophagy"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Liu, S., Li, S., Zhang, G., Tian, A., and Wan, Y. (2022). BIRC5 regulates inflammatory tumor microenvironment-induced aggravation of penile cancer development in vitro and in vivo. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09500-9"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41568-022-00456-3","article-title":"Targeting CDK4 and CDK6 in cancer","volume":"22","author":"Goel","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108944","DOI":"10.1016\/j.celrep.2021.108944","article-title":"Metabolic modulation by CDK4\/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors","volume":"35","author":"Uzhachenko","year":"2021","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, Z., Long, X., Chao, C., Yan, C., Wu, Q., Hua, S., Zhang, Y., Wu, A., and Fang, W. (2014). Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-274"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41591-018-0309-y","article-title":"Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG","volume":"25","author":"Gu","year":"2019","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.2147\/CMAR.S310729","article-title":"HSPA4 Knockdown Retarded Progression and Development of Colorectal Cancer","volume":"13","author":"Zhang","year":"2021","journal-title":"Cancer Manag. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e12315","DOI":"10.7717\/peerj.12315","article-title":"Significant correlation between HSPA4 and prognosis and immune regulation in hepatocellular carcinoma","volume":"9","author":"Shang","year":"2021","journal-title":"PeerJ"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100728","DOI":"10.1016\/j.drup.2020.100728","article-title":"The role of alternative splicing in cancer: From oncogenesis to drug resistance","volume":"53","author":"Sciarrillo","year":"2020","journal-title":"Drug Resist. Updat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s13046-018-0880-6","article-title":"HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma","volume":"37","author":"Xiao","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Schneider, L., Liu, J., Zhang, C., Azoitei, A., Meessen, S., Zheng, X., Cremer, C., Gorzelanny, C., Kempe-Gonzales, S., and Brunner, C. (2021). The Role of Interleukin-1-Receptor-Antagonist in Bladder Cancer Cell Migration and Invasion. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115875"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9267","DOI":"10.1073\/pnas.88.20.9267","article-title":"Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor","volume":"88","author":"Maglione","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.canlet.2004.05.020","article-title":"The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer","volume":"213","author":"Chen","year":"2004","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ccr.2010.11.009","article-title":"HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PlGF","volume":"19","author":"Rolny","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1158\/1078-0432.CCR-15-1839","article-title":"PlGF\/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity","volume":"22","author":"Incio","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Albonici, L., Giganti, M.G., Modesti, A., Manzari, V., and Bei, R. (2019). Multifaceted Role of the Placental Growth Factor (PlGF) in the Antitumor Immune Response and Cancer Progression. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122970"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.2741\/4774","article-title":"Asporin promotes cell proliferation via interacting with PSMD2 in gastric cancer","volume":"24","author":"Li","year":"2019","journal-title":"Front. Biosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1111\/cas.12825","article-title":"Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer","volume":"106","author":"Oguro","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.yexcr.2017.08.028","article-title":"Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma","volume":"359","author":"Zhang","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s00280-018-3759-5","article-title":"SPP1 inhibition improves the cisplatin chemo-sensitivity of cervical cancer cell lines","volume":"83","author":"Chen","year":"2019","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13046-022-02370-w","article-title":"Stanniocalcin 2 (STC2): A universal tumour biomarker and a potential therapeutical target","volume":"41","author":"Qie","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"BSR20194337","DOI":"10.1042\/BSR20194337","article-title":"Mining TCGA database for tumor mutation burden and their clinical significance in bladder cancer","volume":"40","author":"Lv","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1801946","article-title":"Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden","volume":"378","author":"Hellmann","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102990","DOI":"10.1016\/j.ebiom.2020.102990","article-title":"Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma","volume":"60","author":"Sun","year":"2020","journal-title":"eBioMedicine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/s13046-021-02128-w","article-title":"The role of the tumor microbe microenvironment in the tumor immune microenvironment: Bystander, activator, or inhibitor?","volume":"40","author":"Ma","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e49020","DOI":"10.7554\/eLife.49020","article-title":"Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction","volume":"8","author":"Wang","year":"2019","journal-title":"eLife"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1158\/2326-6066.CIR-18-0436","article-title":"Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures","volume":"7","author":"Zeng","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41423-020-00572-w","article-title":"Immunobiology and immunotherapy of HCC: Spotlight on innate and innate-like immune cells","volume":"18","author":"Ruf","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.it.2022.04.010","article-title":"Turning cold tumors hot: From molecular mechanisms to clinical applications","volume":"43","author":"Zhang","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.canlet.2020.03.027","article-title":"Microbiota-derived SSL6 enhances the sensitivity of hepatocellular carcinoma to sorafenib by down-regulating glycolysis","volume":"481","author":"Zhang","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"900713","DOI":"10.3389\/fgene.2022.900713","article-title":"Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma","volume":"13","author":"Ren","year":"2022","journal-title":"Front. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.jtcvs.2017.12.107","article-title":"Nomogram: An analogue tool to deliver digital knowledge","volume":"155","author":"Park","year":"2018","journal-title":"J. Thorac. Cardiovasc. Surg."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:53Z","timestamp":1760143793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/10\/1834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["genes13101834"],"URL":"https:\/\/doi.org\/10.3390\/genes13101834","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,11]]}}}