{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:14:49Z","timestamp":1791519289341,"version":"4.3.4"},"reference-count":36,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82260572"],"award-info":[{"award-number":["82260572"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>The 12-lipoxygenase (12-LOX)\/12-hydroxyeicosatetraenoic acid (12-HETE) pathway is associated with various tumors. M2 macrophages in the tumor microenvironment promote tumorigenesis and progression. However, the role of the 12-LOX\/12-HETE\/G protein-coupled receptor 31 (GPR31) metabolic pathway and its relationship with M2 macrophages remains unclear in pancreatic cancer (PC).<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods<\/jats:title>\n               <jats:p>The expression levels of 12-LOX, GPR31, and 12-HETE were detected in PC and mouse PC models using western blot and enzyme-linked immunosorbent assays (ELISA). <jats:italic>In vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments were conducted using the 12-LOX inhibitor ML355 to investigate the role of the 12-LOX\/12-HETE\/GPR31 metabolic pathway in M2 macrophage polarization and tumor progression through flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), 5-Ethynyl-20-deoxyuridine (EdU) assays, and Transwell experiments.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Results<\/jats:title>\n               <jats:p>The 12-LOX\/12-HETE\/GPR31 metabolic pathway is expressed actively in PC. Inhibition of 12-LOX in a mouse model of pancreatic cancer suppressed the expression of this metabolic pathway, retarded tumor growth, and reduced the polarization of macrophages towards the M2 type. <jats:italic>In vitro<\/jats:italic>, co-culturing PC cell line PANC-1 with macrophages and selectively inhibiting 12-LOX influenced the proliferation, migration, and invasion of PC cells. Inhibiting 12-LOX did not suppress the function of individual PC cells, but it inhibited the development of PC cells co-cultured with macrophages. Moreover, inhibiting 12-LOX reduced the co-cultured M2 macrophages.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusion<\/jats:title>\n               <jats:p>This study, through <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments, reveals that the 12-LOX\/12-HETE\/GPR31 metabolic pathway affects the growth, migration, and invasion of PC by modulating M2 macrophage polarization patterns.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.19963","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:04:46Z","timestamp":1759737886000},"page":"e19963","source":"Crossref","is-referenced-by-count":2,"title":["The 12-LOX\/12-HETE\/GPR31 metabolic pathway promotes tumor-associated macrophage M2 polarization mediated pancreatic cancer development"],"prefix":"10.7717","volume":"13","author":[{"given":"Ying","family":"Yang","sequence":"first","affiliation":[{"name":"First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, General Hospital of Ningxia Medical University, Yinchuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wu","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, General Hospital of Ningxia Medical University, Yinchuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiu","family":"Tan","sequence":"additional","affiliation":[{"name":"First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Huang","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, General Hospital of Ningxia Medical University, Yinchuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"10.7717\/peerj.19963\/ref-1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.21315\/mjms2017.24.5.11","article-title":"Sample size calculation in animal studies using resource equation approach","volume":"24","author":"Arifin","year":"2017","journal-title":"Malaysian Journal of Medical Sciences"},{"key":"10.7717\/peerj.19963\/ref-2","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41389-018-0042-x","article-title":"SNAIL1 action in tumor cells influences macrophage polarization and metastasis in breast cancer through altered GM-CSF secretion","volume":"7","author":"Brenot","year":"2018","journal-title":"Oncogenesis"},{"issue":"4","key":"10.7717\/peerj.19963\/ref-3","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1667\/RR15356.1","article-title":"12-Lipoxygenase is a critical mediator of type II pneumocyte senescence, macrophage polarization and pulmonary fibrosis after irradiation","volume":"192","author":"Chung","year":"2019","journal-title":"Radiation Research"},{"issue":"3","key":"10.7717\/peerj.19963\/ref-4","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth","volume":"41","author":"De\u00a0Visser","year":"2023","journal-title":"Cancer Cell"},{"key":"10.7717\/peerj.19963\/ref-5","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1002\/ijc.28165","article-title":"Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K\/Akt\/NF-\u03baB","volume":"133","author":"Dilly","year":"2013","journal-title":"International Journal of Cancer"},{"key":"10.7717\/peerj.19963\/ref-6","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12943-020-01151-3","article-title":"Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma","volume":"19","author":"Fan","year":"2020","journal-title":"Molecular Cancer"},{"issue":"3","key":"10.7717\/peerj.19963\/ref-7","doi-asserted-by":"publisher","first-page":"5079","DOI":"10.1080\/21655979.2022.2036897","article-title":"Luteolin activates M2 macrophages and suppresses M1 macrophages by upregulation of hsa_circ_0001326 in THP-1 derived macrophages","volume":"13","author":"Gong","year":"2022","journal-title":"Bioengineered"},{"key":"10.7717\/peerj.19963\/ref-8","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1007\/s00280-011-1595-y","article-title":"Role of 12-lipoxygenase in regulation of ovarian cancer cell proliferation and survival","volume":"68","author":"Guo","year":"2011","journal-title":"Cancer Chemotherapy and Pharmacology"},{"issue":"39","key":"10.7717\/peerj.19963\/ref-9","doi-asserted-by":"publisher","first-page":"33832","DOI":"10.1074\/jbc.M110.216564","article-title":"Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid","volume":"286","author":"Guo","year":"2011","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"10.7717\/peerj.19963\/ref-10","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1080\/21505594.2018.1556150","article-title":"Cryptococcus neoformans and Cryptococcus gattii clinical isolates from Thailand display diverse phenotypic interactions with macrophages","volume":"10","author":"Hansakon","year":"2019","journal-title":"Virulence"},{"key":"10.7717\/peerj.19963\/ref-11","doi-asserted-by":"publisher","first-page":"215751","DOI":"10.1016\/j.canlet.2022.215751","article-title":"Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis","volume":"548","author":"He","year":"2022","journal-title":"Cancer Letters"},{"key":"10.7717\/peerj.19963\/ref-12","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1007\/s10555-021-09988-w","article-title":"The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions","volume":"40","author":"Herting","year":"2021","journal-title":"Cancer and Metastasis Reviews"},{"key":"10.7717\/peerj.19963\/ref-13","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1096\/fj.201500076","article-title":"12-HETER1\/ GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression","volume":"30","author":"Honn","year":"2016","journal-title":"FASEB Journal"},{"key":"10.7717\/peerj.19963\/ref-14","doi-asserted-by":"publisher","first-page":"8657","DOI":"10.1007\/s13277-015-4741-z","article-title":"The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer","volume":"37","author":"Hu","year":"2016","journal-title":"Tumour Biology"},{"issue":"6","key":"10.7717\/peerj.19963\/ref-15","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1593\/neo.04286","article-title":"Overexpression of 12\/15-lipoxygenase, an ortholog of human 15-lipoxygenase-1, in the prostate tumors of TRAMP mice","volume":"6","author":"Kelavkar","year":"2004","journal-title":"Neoplasia"},{"issue":"5","key":"10.7717\/peerj.19963\/ref-16","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1172\/JCI44751","article-title":"Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse","volume":"121","author":"Kerjaschki","year":"2011","journal-title":"Journal of Clinical Investigation"},{"issue":"1","key":"10.7717\/peerj.19963\/ref-17","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1158\/0008-5472.CAN-13-1196","article-title":"Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population","volume":"74","author":"Laoui","year":"2014","journal-title":"Cancer Research"},{"key":"10.7717\/peerj.19963\/ref-18","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.ccr.2011.03.009","article-title":"Stat3\/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer","volume":"19","author":"Lesina","year":"2011","journal-title":"Cancer Cell"},{"issue":"7","key":"10.7717\/peerj.19963\/ref-19","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1016\/j.celrep.2017.04.052","article-title":"The presence of interleukin-13 at pancreatic ADM\/PanIN lesions alters macrophage populations and mediates pancreatic tumorigenesis","volume":"19","author":"Liou","year":"2017","journal-title":"Cell Reports"},{"issue":"3","key":"10.7717\/peerj.19963\/ref-20","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1083\/jcb.201301001","article-title":"Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-\u03baB and MMPs","volume":"202","author":"Liou","year":"2013","journal-title":"Journal of Cell Biology"},{"key":"10.7717\/peerj.19963\/ref-21","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.redox.2015.08.006","article-title":"The role of lipoxygenases in pathophysiology; new insights and future perspectives","volume":"6","author":"Mashima","year":"2015","journal-title":"Redox Biology"},{"issue":"27","key":"10.7717\/peerj.19963\/ref-22","doi-asserted-by":"publisher","first-page":"18601","DOI":"10.1074\/jbc.M601887200","article-title":"Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells","volume":"281","author":"Nie","year":"2006","journal-title":"Journal of Biological Chemistry"},{"key":"10.7717\/peerj.19963\/ref-23","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1007\/s10555-007-9098-3","article-title":"Lipoxygenase metabolism: roles in tumor progression and survival","volume":"26","author":"Pidgeon","year":"2007","journal-title":"Cancer and Metastasis Reviews"},{"issue":"4","key":"10.7717\/peerj.19963\/ref-24","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.bbalip.2014.10.008","article-title":"Biosynthesis, and effects, biological and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid","volume":"1851","author":"Powell","year":"2015","journal-title":"Biochimica Et Biophysica Acta\/General Subjects"},{"issue":"4","key":"10.7717\/peerj.19963\/ref-25","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"10.7717\/peerj.19963\/ref-26","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12943-022-01618-5","article-title":"LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer","volume":"21","author":"Sun","year":"2022","journal-title":"Molecular Cancer"},{"issue":"9791","key":"10.7717\/peerj.19963\/ref-27","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/S0140-6736(10)62307-0","article-title":"Pancreatic cancer","volume":"378","author":"Vincent","year":"2011","journal-title":"Lancet"},{"key":"10.7717\/peerj.19963\/ref-28","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Von\u00a0Hoff","year":"2013","journal-title":"New England Journal of Medicine"},{"key":"10.7717\/peerj.19963\/ref-29","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1007\/s11523-020-00751-9","article-title":"Targeting TAM to tame pancreatic cancer","volume":"15","author":"Von Itzstein","year":"2020","journal-title":"Targeted Oncology"},{"key":"10.7717\/peerj.19963\/ref-30","doi-asserted-by":"publisher","first-page":"101812","DOI":"10.1016\/j.tice.2022.101812","article-title":"The serum soluble Klotho alleviates cardiac aging and regulates M2a\/M2c macrophage polarization via inhibiting TLR4\/Myd88\/NF-\u03baB pathway","volume":"76","author":"Wang","year":"2022","journal-title":"Tissue and Cell"},{"key":"10.7717\/peerj.19963\/ref-31","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1186\/s13046-019-1480-9","article-title":"Ischemia reperfusion injury promotes recurrence of hepatocellular carcinoma in fatty liver via ALOX12-12HETE-GPR31 signaling axis","volume":"38","author":"Yang","year":"2019","journal-title":"Journal of Experimental & Clinical Cancer Research"},{"key":"10.7717\/peerj.19963\/ref-32","doi-asserted-by":"publisher","first-page":"5551","DOI":"10.2147\/OTT.S201373","article-title":"12-Lipoxygenase promotes epithelial-mesenchymal transition via the Wnt\/\u03b2-catenin signaling pathway in gastric cancer cells","volume":"12","author":"Yang","year":"2019","journal-title":"OncoTargets and Therapy"},{"key":"10.7717\/peerj.19963\/ref-33","doi-asserted-by":"publisher","first-page":"1273099","DOI":"10.1155\/2024\/1273099","article-title":"IL-33-pretreated mesenchymal stem cells attenuate acute liver failure by improving homing and polarizing M2 macrophages","volume":"2024","author":"Yuan","year":"2024","journal-title":"Stem Cells International"},{"key":"10.7717\/peerj.19963\/ref-34","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nm.4451","article-title":"An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury","volume":"24","author":"Zhang","year":"2018","journal-title":"Nature Medicine"},{"key":"10.7717\/peerj.19963\/ref-35","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.3892\/ol.2018.8808","article-title":"12-Lipoxygenase promotes invasion and metastasis of human gastric cancer cells via epithelial-mesenchymal transition","volume":"16","author":"Zhong","year":"2018","journal-title":"Oncology Letters"},{"key":"10.7717\/peerj.19963\/ref-36","doi-asserted-by":"publisher","first-page":"120546","DOI":"10.1016\/j.biomaterials.2020.120546","article-title":"Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment","volume":"268","author":"Zhou","year":"2021","journal-title":"Biomaterials"}],"container-title":["PeerJ"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/peerj.com\/articles\/19963.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19963.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19963.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/19963.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:04:47Z","timestamp":1759737887000},"score":1,"resource":{"primary":{"URL":"https:\/\/peerj.com\/articles\/19963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,6]]},"references-count":36,"alternative-id":["10.7717\/peerj.19963"],"URL":"https:\/\/doi.org\/10.7717\/peerj.19963","archive":["CLOCKSS","LOCKSS","Portico"],"relation":{},"ISSN":["2167-8359"],"issn-type":[{"value":"2167-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,6]]},"article-number":"e19963"}}