{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T05:38:22Z","timestamp":1775713102708,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T00:00:00Z","timestamp":1703721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI Grant-in-Aid for Scientific Research","award":["JP 20K07653"],"award-info":[{"award-number":["JP 20K07653"]}]},{"name":"JSPS KAKENHI Grant-in-Aid for Scientific Research","award":["JP21gm6210025"],"award-info":[{"award-number":["JP21gm6210025"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP 20K07653"],"award-info":[{"award-number":["JP 20K07653"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21gm6210025"],"award-info":[{"award-number":["JP21gm6210025"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.<\/jats:p>","DOI":"10.3390\/cancers16010159","type":"journal-article","created":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T09:56:27Z","timestamp":1703757387000},"page":"159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-3054","authenticated-orcid":false,"given":"Sadahiro","family":"Iwabuchi","sequence":"first","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Wakayama 641-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0910-4514","authenticated-orcid":false,"given":"Kenta","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Ishikawa, Kanazawa 920-0934, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4927-1704","authenticated-orcid":false,"given":"Kazunori","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Kanazawa 920-0934, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4414-5530","authenticated-orcid":false,"given":"Akihisa","family":"Nagatsu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Sapporo 060-8648, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Imafuku","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Wakayama 641-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeyuki","family":"Shichino","sequence":"additional","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Disease, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouji","family":"Matsushima","sequence":"additional","affiliation":[{"name":"Division of Molecular Regulation of Inflammatory and Immune Disease, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Noda 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-3678","authenticated-orcid":false,"given":"Akinobu","family":"Taketomi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Sapporo 060-8648, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3050-5854","authenticated-orcid":false,"given":"Masao","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Kanazawa 920-0934, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Wakayama 641-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1111\/j.1478-3231.2012.02786.x","article-title":"Hepatocellular adenoma subtypes: The impact of overweight and obesity","volume":"32","author":"Taouji","year":"2012","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1053\/j.gastro.2009.07.061","article-title":"A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas","volume":"137","author":"Dokmak","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"648131","DOI":"10.1155\/2012\/648131","article-title":"Overview of hepatocellular adenoma in Japan","volume":"2012","author":"Sasaki","year":"2012","journal-title":"Int. J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1053\/j.gastro.2016.11.042","article-title":"Molecular Classification of Hepatocellular Adenoma Associates with Risk Factors, Bleeding, and Malignant Transformation","volume":"152","author":"Nault","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/his.14605","article-title":"Hepatocellular adenoma: What we know, what we do not know, and why it matters","volume":"80","author":"Gouw","year":"2022","journal-title":"Histopathology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.3748\/wjg.v28.i14.1384","article-title":"Hepatocellular adenoma: Where are we now?","volume":"28","author":"Wang","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-981-13-6037-4_4","article-title":"Nx1-Seq (Well Based Single-Cell Analysis System)","volume":"1129","author":"Hashimoto","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14225","DOI":"10.1038\/s41598-017-14676-3","article-title":"Comprehensive single-cell transcriptome analysis reveals heterogeneity in endometrioid adenocarcinoma tissues","volume":"7","author":"Hashimoto","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12944-016-0400-7","article-title":"Promoting effect of hepatitis B virus on the expressoin of phospholipase A2 group IIA","volume":"16","author":"Zhu","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1042\/bj3360611","article-title":"Activation of phospholipase A2 in human neutrophils by polyunsaturated fatty acids and its role in stimulation of superoxide production","volume":"336","author":"Robinson","year":"1998","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.biochi.2010.03.015","article-title":"Emerging roles of secreted phospholipase A2 enzymes: Lessons from transgenic and knockout mice","volume":"92","author":"Murakami","year":"2010","journal-title":"Biochimie"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.jtcvs.2009.10.061","article-title":"Modulation of growth in human esophageal adenocarcinoma cells by group IIa secretory phospholipase A(2)","volume":"139","author":"Mauchley","year":"2010","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wong, K.K., Rostomily, R., and Wong, S.T.C. (2019). Prognostic Gene Discovery in Glioblastoma Patients using Deep Learning. Cancers, 11.","DOI":"10.3390\/cancers11010053"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/his.12613","article-title":"PLA2G2A overexpression is associated with poor therapeutic response and inferior outcome in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy","volume":"66","author":"He","year":"2015","journal-title":"Histopathology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, M., Xiang, R., Glorieux, C., and Huang, P. (2022). PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911721"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16203","DOI":"10.1073\/pnas.212646299","article-title":"Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis","volume":"99","author":"Leung","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1158\/0008-5472.CAN-07-6517","article-title":"Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel beta-catenin\/TCF target gene","volume":"68","author":"Ganesan","year":"2008","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1365-2559.2011.03913.x","article-title":"Phospholipase A2 group IIA expression correlates with prolonged survival in gastric cancer","volume":"59","author":"Xing","year":"2011","journal-title":"Histopathology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4103\/1735-1995.177358","article-title":"The effect of omega-fatty acids on the expression of phospholipase A2 group 2A in human gastric cancer patients","volume":"21","author":"Shariati","year":"2016","journal-title":"J. Res. Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s12253-013-9652-y","article-title":"Plasma levels of phospholipase A2-IIA in patients with different types of malignancies: Prognosis and association with inflammatory and coagulation biomarkers","volume":"19","author":"Menschikowski","year":"2013","journal-title":"Pathol. Oncol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/path.2440","article-title":"The Human Protein Atlas\u2014A tool for pathology","volume":"216","author":"Ponten","year":"2008","journal-title":"J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e27633","DOI":"10.2196\/27633","article-title":"Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation","volume":"23","author":"Lanczky","year":"2021","journal-title":"J. Med. Internet Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1002\/hep.28638","article-title":"Genotype-phenotype correlation of CTNNB1 mutations reveals different ss-catenin activity associated with liver tumor progression","volume":"64","author":"Rebouissou","year":"2016","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1038\/s41467-020-15846-0","article-title":"LGR5 marks targetable tumor-initiating cells in mouse liver cancer","volume":"11","author":"Cao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"He, J., Han, J., Lin, K., Wang, J., Li, G., Li, X., and Gao, Y. (2023). PTEN\/AKT and Wnt\/beta-catenin signaling pathways regulate the proliferation of Lgr5+ cells in liver cancer. Biochem. Biophys. Res. Commun., 683.","DOI":"10.1016\/j.bbrc.2023.10.049"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"861","DOI":"10.7150\/ijbs.56091","article-title":"PTEN-mediated AKT\/beta-catenin signaling enhances the proliferation and expansion of Lgr5+ hepatocytes","volume":"17","author":"Han","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"G462","DOI":"10.1152\/ajpgi.00358.2018","article-title":"Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals","volume":"316","author":"Suppli","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/1\/159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:43:39Z","timestamp":1760132619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/1\/159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,28]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cancers16010159"],"URL":"https:\/\/doi.org\/10.3390\/cancers16010159","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,28]]}}}