{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T12:42:39Z","timestamp":1784119359870,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81803272"],"award-info":[{"award-number":["81803272"]}]},{"name":"National Natural Science Foundation of China","award":["81872685"],"award-info":[{"award-number":["81872685"]}]},{"name":"National Natural Science Foundation of China","award":["2020JJ5385"],"award-info":[{"award-number":["2020JJ5385"]}]},{"name":"National Natural Science Foundation of China","award":["202212045173"],"award-info":[{"award-number":["202212045173"]}]},{"name":"National Natural Science Foundation of China","award":["KF2022004"],"award-info":[{"award-number":["KF2022004"]}]},{"name":"Natural Science Foundation of Hunan Province","award":["81803272"],"award-info":[{"award-number":["81803272"]}]},{"name":"Natural Science Foundation of Hunan Province","award":["81872685"],"award-info":[{"award-number":["81872685"]}]},{"name":"Natural Science Foundation of Hunan Province","award":["2020JJ5385"],"award-info":[{"award-number":["2020JJ5385"]}]},{"name":"Natural Science Foundation of Hunan Province","award":["202212045173"],"award-info":[{"award-number":["202212045173"]}]},{"name":"Natural Science Foundation of Hunan Province","award":["KF2022004"],"award-info":[{"award-number":["KF2022004"]}]},{"name":"Foundation of Hunan Provincial Health Commission","award":["81803272"],"award-info":[{"award-number":["81803272"]}]},{"name":"Foundation of Hunan Provincial Health Commission","award":["81872685"],"award-info":[{"award-number":["81872685"]}]},{"name":"Foundation of Hunan Provincial Health Commission","award":["2020JJ5385"],"award-info":[{"award-number":["2020JJ5385"]}]},{"name":"Foundation of Hunan Provincial Health Commission","award":["202212045173"],"award-info":[{"award-number":["202212045173"]}]},{"name":"Foundation of Hunan Provincial Health Commission","award":["KF2022004"],"award-info":[{"award-number":["KF2022004"]}]},{"name":"The open project of Hunan Normal University School of Medicine","award":["81803272"],"award-info":[{"award-number":["81803272"]}]},{"name":"The open project of Hunan Normal University School of Medicine","award":["81872685"],"award-info":[{"award-number":["81872685"]}]},{"name":"The open project of Hunan Normal University School of Medicine","award":["2020JJ5385"],"award-info":[{"award-number":["2020JJ5385"]}]},{"name":"The open project of Hunan Normal University School of Medicine","award":["202212045173"],"award-info":[{"award-number":["202212045173"]}]},{"name":"The open project of Hunan Normal University School of Medicine","award":["KF2022004"],"award-info":[{"award-number":["KF2022004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Exosome complex (EXOSC) is a multiprotein complex that was originally discovered as the machinery of RNA degradation. Interestingly, recent studies have reported that EXOSC family members (EXOSCs) are associated with various human diseases, including cancers. It will be interesting to investigate whether EXOSCs are related to the processes of hepatocellular carcinoma (HCC). In this study, multiple public databases and experimental validation were utilized to systemically investigate the role of EXOSCs, especially EXOSC5, in HCC. It is worth considering that the mRNA and protein levels of many EXOSCs were elevated in HCC, although there were some differences in the results from different database analyses. The over-expression of EXOSCs could predict HCC to some extent, as evidenced by the positive correlation between the elevated EXOSCs and alpha fetoprotein (AFP) levels, as well as with a high accuracy, as shown by the receiver operating characteristic curve analysis. Additionally, higher mRNA expressions of specific EXOSCs were significantly related to clinical cancer stage, shorter overall survival and disease-free survival in HCC patients. A moderate mutation rate of EXOSCs was also observed in HCC. Furthermore, a gene functional enrichment analysis indicated that EXOSCs were mainly involved in the metabolism of RNA. Moreover, we revealed that the expression of EXOSCs is remarkably related to immune cell infiltration. Finally, EXOSC5 was upregulated in HCC tissues and cell lines, promoting cell growth and proliferation via activated signal transducer and activator of transcription 3 (STAT3). The bioinformatic analyses, following verification in situ and in vitro, provided a direction for further functions and underlying mechanism of EXOSCs in HCC.<\/jats:p>","DOI":"10.3390\/ijms232012161","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T20:53:29Z","timestamp":1665608009000},"page":"12161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Integrated Bioinformatic Investigation of EXOSCs in Hepatocellular Carcinoma Followed by the Preliminary Validation of EXOSC5 in Cell Proliferation"],"prefix":"10.3390","volume":"23","author":[{"given":"Yujing","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4874-3626","authenticated-orcid":false,"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1001\/jamasurg.2018.4334","article-title":"Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China","volume":"154","author":"Xu","year":"2019","journal-title":"JAMA Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.21037\/jgo.2016.09.07","article-title":"Hepatocellular carcinoma (HCC): Beyond sorafenib-chemotherapy","volume":"8","author":"Kim","year":"2017","journal-title":"J. Gastrointest Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/hep.29485","article-title":"Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis","volume":"67","author":"Kulik","year":"2018","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1158\/0008-5472.CAN-20-0225","article-title":"Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression","volume":"80","author":"Midorikawa","year":"2020","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wong, L.S., and Wong, C.M. (2021). Decoding the Roles of Long Noncoding RNAs in Hepatocellular Carcinoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063137"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1136\/gutjnl-2017-315084","article-title":"Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma","volume":"68","author":"Ren","year":"2019","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12943-022-01500-4","article-title":"The role of m6A RNA methylation in cancer metabolism","volume":"21","author":"An","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.cell.2009.01.019","article-title":"The many pathways of RNA degradation","volume":"136","author":"Houseley","year":"2009","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/cge.13549","article-title":"Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families","volume":"95","author":"Beheshtian","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.7150\/jca.69166","article-title":"EXOSC5 promotes proliferation of gastric cancer through regulating AKT\/STAT3 signaling pathways","volume":"13","author":"Chen","year":"2022","journal-title":"J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e69454","DOI":"10.7554\/eLife.69454","article-title":"Exosome component 1 cleaves single-stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor","volume":"10","author":"Liu","year":"2021","journal-title":"Elife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.cell.2016.05.046","article-title":"Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression","volume":"165","author":"Goodarzi","year":"2016","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5100","DOI":"10.1111\/cas.15157","article-title":"Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer","volume":"112","author":"Tsuda","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1002\/mc.22896","article-title":"EXOSC4 functions as a potential oncogene in development and progression of colorectal cancer","volume":"57","author":"Pan","year":"2018","journal-title":"Mol. Carcinog."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"643","DOI":"10.3389\/fonc.2019.00643","article-title":"EXOSC5 as a Novel Prognostic Marker Promotes Proliferation of Colorectal Cancer via Activating the ERK and AKT Pathways","volume":"9","author":"Pan","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"953","DOI":"10.7150\/ijms.50704","article-title":"Integral Analysis of the RNA Binding Protein-associated Prognostic Model for Renal Cell Carcinoma","volume":"18","author":"Qin","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41392-022-00872-9","article-title":"Targeting polarized phenotype of microglia via IL6\/JAK2\/STAT3 signaling to reduce NSCLC brain metastasis","volume":"7","author":"Jin","year":"2022","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/cr.2010.183","article-title":"NF-\u03baB and STAT3\u2014Key players in liver inflammation and cancer","volume":"21","author":"He","year":"2011","journal-title":"Cell Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12943-020-01258-7","article-title":"Targeting STAT3 in Cancer Immunotherapy","volume":"19","author":"Zou","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.jhep.2017.06.005","article-title":"Reply to: \u201cHepatocellular carcinoma (HCC) in the absence of cirrhosis in patients with chronic hepatitis B virus infection\u201d","volume":"67","author":"Chayanupatkul","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41419-020-03030-7","article-title":"AFP promotes HCC progression by suppressing the HuR-mediated Fas\/FADD apoptotic pathway","volume":"11","author":"Chen","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Foerster, F., and Galle, P.R. (2021). The Current Landscape of Clinical Trials for Systemic Treatment of HCC. Cancers, 13.","DOI":"10.3390\/cancers13081962"},{"key":"ref_23","first-page":"e1166","article-title":"Modeling Pathogenic Variants in the RNA Exosome","volume":"7","author":"Slavotinek","year":"2020","journal-title":"RNA Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1126\/sciadv.abe5043","article-title":"A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer","volume":"7","author":"Shi","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9275","DOI":"10.1038\/s41598-020-66455-2","article-title":"EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells","volume":"10","author":"Yoshino","year":"2020","journal-title":"Sci Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/s41388-019-1026-9","article-title":"Comprehensive characterization of the rRNA metabolism-related genes in human cancer","volume":"39","author":"Cui","year":"2020","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1261\/rna.064626.117","article-title":"The RNA exosome and RNA exosome-linked disease","volume":"24","author":"Morton","year":"2018","journal-title":"Rna"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.2174\/0929866528666211105112927","article-title":"Detection of Melanogenesis and Anti-Apoptosis-Associated Melanoma Factors: Array CGH and PPI Mapping Integrating Study","volume":"28","author":"Yin","year":"2021","journal-title":"Protein Pept. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cell.2015.04.034","article-title":"RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity","volume":"161","author":"Pefanis","year":"2015","journal-title":"Cell"},{"key":"ref_30","first-page":"77","article-title":"Innate and adaptive immune cells in Tumor microenvironment","volume":"1","author":"Shrihari","year":"2021","journal-title":"Gulf. J. Oncolog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/cr.2016.157","article-title":"Dendritic cell-based immunotherapy","volume":"27","author":"Sabado","year":"2017","journal-title":"Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.canlet.2019.03.018","article-title":"Harnessing immune checkpoints in myeloid lineage cells for cancer immunotherapy","volume":"452","author":"Park","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","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":"ref_34","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1093\/nar\/gkf545","article-title":"Temperature-sensitive mutants of the exosome subunit Rrp43p show a deficiency in mRNA degradation and no longer interact with the exosome","volume":"30","author":"Oliveira","year":"2002","journal-title":"Nucleic. Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1128\/JVI.02203-18","article-title":"Peroxiredoxin 1, a Novel HBx-Interacting Protein, Interacts with Exosome Component 5 and Negatively Regulates Hepatitis B Virus (HBV) Propagation through Degradation of HBV RNA","volume":"93","author":"Deng","year":"2019","journal-title":"J. Virol."},{"key":"ref_36","first-page":"5517","article-title":"CML28 is a broadly immunogenic antigen, which is overexpressed in tumor cells","volume":"62","author":"Yang","year":"2002","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4504","DOI":"10.1158\/1078-0432.CCR-05-0036","article-title":"Graft-versus-leukemia target antigens in chronic myelogenous leukemia are expressed on myeloid progenitor cells","volume":"11","author":"Wu","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1007\/s00262-006-0152-8","article-title":"Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28","volume":"55","author":"Han","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_39","first-page":"4795535","article-title":"A Novel Reformed Reduced Kernel Extreme Learning Machine with RELIEF-F for Classification","volume":"2022","author":"Liu","year":"2022","journal-title":"Comput. Intell Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: An update to the integrated cancer data analysis platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.neo.2017.05.002","article-title":"UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses","volume":"19","author":"Chandrashekar","year":"2017","journal-title":"Neoplasia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6340","DOI":"10.1126\/science.aal3321","article-title":"A subcellular map of the human proteome","volume":"356","author":"Thul","year":"2017","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6352","DOI":"10.1126\/science.aan2507","article-title":"A pathology atlas of the human cancer transcriptome","volume":"357","author":"Uhlen","year":"2017","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:52:42Z","timestamp":1760143962000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,12]]},"references-count":45,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012161"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012161","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,12]]}}}