{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:56:40Z","timestamp":1790535400488,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The tumor microenvironment, particularly M2\u2010polarized tumor\u2010associated macrophages (TAMs), plays a critical role in cervical cancer (CC) progression. Long non\u2010coding RNAs (lncRNAs) are emerging as potential regulators of macrophage function. This study aimed to investigate the function and mechanism of the lncRNA GNAS\u2010AS1 in M2\u2010like TAMs and its impact on CC progression. M2 macrophages were isolated from clinical CC and adjacent normal tissues. In vitro polarization models were established using THP\u20101 cells treated with PMA, LPS\/IFN\u2010\u03b3 (M1), or IL\u20104 (M2). Functional assays (CCK\u20108, colony formation, Transwell) were used to assess cancer cell malignant phenotypes after co\u2010culture with macrophages or their supernatants. Mechanistic studies included RNA pulldown, luciferase reporter assays, and western blot. Xenograft and metastatic mouse models were employed to validate the findings in vivo. GNAS\u2010AS1 expression was found to be elevated in M2 TAMs isolated from CC tissues compared to other immune cells and normal tissue\u2010derived M2 macrophages, and its expression correlated with M2 marker levels. In vitro, GNAS\u2010AS1 knockdown attenuated the M2 phenotype, as evidenced by reduced expression of characteristic M2 markers and impaired ability to promote CC cell proliferation and migration. In vivo models showed that GNAS\u2010AS1 knockdown in M2 macrophages suppressed tumor growth and metastasis. Mechanistically, data from binding and rescue experiments are consistent with a model whereby GNAS\u2010AS1 may function by sequestering miR\u2010518c\u20105p, leading to increased expression of its target, FBXO38, and associated changes in MAPK signaling. These findings suggest that GNAS\u2010AS1 may contribute to the maintenance of M2\u2010like characteristics in TAMs and facilitate CC progression, potentially through a mechanism involving miR\u2010518c\u20105p sequestering, FBXO38 upregulation, and subsequent modulation of MAPK signaling.<\/jats:p>","DOI":"10.1002\/mc.70110","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:09:25Z","timestamp":1790532565000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GNAS\u2010AS1 Promotes M2\u2010Like Macrophage Polarization, Contributing to Cervical Cancer Growth, Angiogenesis, and Metastasis Through the miR\u2010518c\u20105p\/FBXO38 Axis and MAPK Signaling"],"prefix":"10.1002","author":[{"given":"Lili","family":"Zhang","sequence":"first","affiliation":[{"name":"Yancheng Maternity and Child Health Care Hospital Affiliated to Yangzhou University Yancheng China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhangjiagang Hospital Affiliated to Soochow University Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhangjiagang Hospital Affiliated to Soochow University Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Jia","sequence":"additional","affiliation":[{"name":"Zhangjiagang Hospital Affiliated to Soochow University Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhangjiagang Hospital Affiliated to Soochow University Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhangjiagang Hospital Affiliated to Soochow University Zhangjiagang Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"issue":"2","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/ijc.35369","article-title":"Global Landscape of Cervical Cancer Incidence and Mortality in 2022 and Predictions to 2030: The Urgent Need to Address Inequalities in Cervical Cancer","volume":"157","author":"Li Z.","year":"2025","journal-title":"International Journal of Cancer"},{"issue":"4","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.hoc.2024.03.005","article-title":"Cervical Cancer","volume":"38","author":"Sahasrabuddhe V. V.","year":"2024","journal-title":"Hematology\/Oncology Clinics of North America"},{"key":"e_1_2_12_4_1","unstructured":"\u201cCervical Cancer Causes Risk Factors and Prevention: Patient Version \u201d inPDQ Cancer Information Summaries(National Cancer Institute (US) 2002). [Updated: August 2 2024]. Available from:https:\/\/www.cancer.gov\/types\/cervical\/patient\/cervical-prevention-pdq."},{"key":"e_1_2_12_5_1","unstructured":"\u201cCervical Cancer Treatment: Patient Version \u201d inPDQ Cancer Information Summaries(National Cancer Institute (US) 2002). [Updated: April 3 2025]. Available from:https:\/\/www.cancer.gov\/types\/cervical\/patient\/cervical-treatment-pdq."},{"issue":"4","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ijo.2025.5735","article-title":"Epigenetic and Epitranscriptomic Role of lncRNA in Carcinogenesis (Review)","volume":"66","author":"Dai C.","year":"2025","journal-title":"International Journal of Oncology"},{"issue":"4","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s12032-025-02641-4","article-title":"Tumor Microenvironment: Recent Advances in Understanding and Its Role in Modulating Cancer Therapies","volume":"42","author":"Shah D. D.","year":"2025","journal-title":"Medical Oncology"},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","DOI":"10.1155\/2020\/6842963","article-title":"Research Progress on Tumor\u2010Associated Macrophages and Inflammation in Cervical Cancer","volume":"2020","author":"Liu Y.","year":"2020","journal-title":"BioMed Research International"},{"issue":"1","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s12094-024-03587-1","article-title":"Clinicopathologic and Prognostic Significance of Tumor\u2010Associated Macrophages in Cervical Cancer: A Systematic Review and Meta\u2010Analysis","volume":"27","author":"Lin X.","year":"2025","journal-title":"Clinical and Translational Oncology"},{"issue":"7","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2025-011948","article-title":"Targeting HK3 in Tumor\u2010Associated Macrophages Enhances Antitumor Immunity Through Augmenting Antigen Cross\u2010Presentation in Cervical Cancer","volume":"13","author":"Yang Y.","year":"2025","journal-title":"Journal for Immunotherapy of Cancer"},{"issue":"19","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"23169","DOI":"10.18632\/aging.203609","article-title":"LncRNA\u2010SNHG1 Promotes Macrophage M2\u2010Like Polarization and Contributes to Breast Cancer Growth and Metastasis","volume":"13","author":"Zong S.","year":"2021","journal-title":"Aging"},{"issue":"1","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11010-023-04709-z","article-title":"LncRNA BANCR Promotes the Colorectal Cancer Metastasis Through Accelerating Exosomes\u2010Mediated M2 Macrophage Polarization via Regulating RhoA\/ROCK Signaling","volume":"479","author":"Ding A. X.","year":"2024","journal-title":"Molecular and Cellular Biochemistry"},{"issue":"7","key":"e_1_2_12_13_1","doi-asserted-by":"crossref","DOI":"10.1042\/BSR20200626","article-title":"LncRNA GNAS\u2010AS1 Facilitates ER+ Breast Cancer Cells Progression by Promoting M2 Macrophage Polarization via Regulating miR\u2010433\u20103p\/GATA3 Axis","volume":"40","author":"Liu S. Q.","year":"2020","journal-title":"Bioscience Reports"},{"issue":"1","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10142-019-00696-x","article-title":"GNAS\u2010AS1\/miR\u20104319\/NECAB3 Axis Promotes Migration and Invasion of Non\u2010Small Cell Lung Cancer Cells by Altering Macrophage Polarization","volume":"20","author":"Li Z.","year":"2020","journal-title":"Functional & Integrative Genomics"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","DOI":"10.3389\/pore.2022.1610493","article-title":"Identification of Diagnostic Exosomal LncRNA\u2010miRNA\u2010mRNA Biomarkers in Colorectal Cancer Based on the ceRNA Network","volume":"28","author":"Zhao Y.","year":"2022","journal-title":"Pathology and Oncology Research"},{"issue":"1","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12864-023-09306-4","article-title":"Identification of lncRNA, miRNA and mRNA Expression Profiles and ceRNA Networks in Small Cell Lung Cancer","volume":"24","author":"Zhang C.","year":"2023","journal-title":"BMC Genomics"},{"issue":"1","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-025-01698-5","article-title":"LncRNA NEAT1 Regulation of the miR\u2010101\u20103p\/RAC1 Axis Affects Cervical Cancer Aerobic Glycolysis and Progression","volume":"15","author":"Cao L.","year":"2025","journal-title":"Scientific Reports"},{"key":"e_1_2_12_18_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2025.1530677","article-title":"LncRNA HIF1A\u2010AS2 Acts as an Oncogene to Regulate Malignant Phenotypes in Cervical Cancer","volume":"15","author":"Liu Y.","year":"2025","journal-title":"Frontiers in Oncology"},{"issue":"1","key":"e_1_2_12_19_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s13205-023-03863-x","article-title":"LncRNA BCRT1 Depletion Suppresses Cervical Cancer Cell Growth via Sponging miR\u2010432\u20105p\/CCR7 Axis","volume":"14","author":"Wang X.","year":"2024","journal-title":"3 Biotech"},{"key":"e_1_2_12_20_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cimid.2019.101355","article-title":"Comparison of Human Monocyte Derived Macrophages and THP1\u2010Like Macrophages as In Vitro Models for M. tuberculosis Infection","volume":"67","author":"Madhvi A.","year":"2019","journal-title":"Comparative Immunology, Microbiology and Infectious Diseases"},{"key":"e_1_2_12_21_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3389\/fphar.2018.00071","article-title":"Convenience Versus Biological Significance: Are PMA\u2010Differentiated THP\u20101 Cells a Reliable Substitute for Blood\u2010Derived Macrophages When Studying In Vitro Polarization?","volume":"9","author":"Tedesco S.","year":"2018","journal-title":"Frontiers in Pharmacology"},{"issue":"11","key":"e_1_2_12_22_1","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/s41423-023-01081-2","article-title":"FBXO38 Regulates Macrophage Polarization to Control the Development of Cancer and Colitis","volume":"20","author":"Zheng X.","year":"2023","journal-title":"Cellular & Molecular Immunology"},{"issue":"16","key":"e_1_2_12_23_1","article-title":"Single\u2010Cell Dissection of Cervical Cancer Reveals Key Subsets of the Tumor Immune Microenvironment","volume":"42","author":"Cao G.","year":"2023","journal-title":"EMBO Journal"},{"issue":"1","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor\u2010Associated Macrophages: From Mechanisms to Therapy","volume":"41","author":"Noy R.","year":"2014","journal-title":"Immunity"},{"issue":"6","key":"e_1_2_12_25_1","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.3390\/cancers12061411","article-title":"Transcriptional, Epigenetic and Metabolic Programming of Tumor\u2010Associated Macrophages","volume":"12","author":"Larionova I.","year":"2020","journal-title":"Cancers"},{"issue":"3","key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1097\/CMR.0000000000000352","article-title":"M1 and M2 Macrophages' Clinicopathological Significance in Cutaneous Melanoma","volume":"27","author":"Falleni M.","year":"2017","journal-title":"Melanoma Research"},{"issue":"18","key":"e_1_2_12_27_1","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.7150\/jca.21444","article-title":"Clinical Significance of CD163+ and CD68+ Tumor\u2010Associated Macrophages in High\u2010Risk HPV\u2010Related Cervical Cancer","volume":"8","author":"Chen X. J.","year":"2017","journal-title":"Journal of Cancer"},{"issue":"1","key":"e_1_2_12_28_1","doi-asserted-by":"crossref","DOI":"10.1515\/med-2023-0740","article-title":"Long Non\u2010Coding RNA GNAS\u2010AS1 Knockdown Inhibits Proliferation and Epithelial\u2010Mesenchymal Transition of Lung Adenocarcinoma Cells via the MicroRNA\u2010433\u20103p\/Rab3A Axis","volume":"18","author":"He J.","year":"2023","journal-title":"Open Medicine"},{"issue":"1","key":"e_1_2_12_29_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/s13018-021-02611-2","article-title":"Biomarker Potential of lncRNA GNAS\u2010AS1 in Osteosarcoma Prognosis and Effect on Cellular Function","volume":"16","author":"Mi Z.","year":"2021","journal-title":"Journal of Orthopaedic Surgery and Research"},{"issue":"6","key":"e_1_2_12_30_1","first-page":"3077","article-title":"Long Non\u2010Coding RNA GNAS\u2010AS1 Promotes Cell Migration and Invasion via Regulating Wnt\/\u03b2\u2010Catenin Pathway in Nasopharyngeal Carcinoma","volume":"24","author":"Wang X. Q.","year":"2020","journal-title":"European Review for Medical and Pharmacological Sciences"},{"issue":"4","key":"e_1_2_12_31_1","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.ncrna.2024.06.002","article-title":"New Mechanism of LncRNA: In Addition to Act as a ceRNA","volume":"9","author":"Zhang J.","year":"2024","journal-title":"Non\u2010Coding RNA Research"},{"issue":"1","key":"e_1_2_12_32_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.7555\/JBR.37.20230097","article-title":"LncRNA IDH1\u2010AS1 Sponges miR\u2010518c\u20105p to Suppress Proliferation of Epithelial Ovarian Cancer Cell by Targeting RMB47","volume":"38","author":"Zhou J.","year":"2024","journal-title":"Journal of Biomedical Research"},{"key":"e_1_2_12_33_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fgene.2020.00009","article-title":"Hsa_Circ_0007843 Acts as a mIR\u2010518c\u20105p Sponge to Regulate the Migration and Invasion of Colon Cancer SW480 Cells","volume":"11","author":"He J. H.","year":"2020","journal-title":"Frontiers in Genetics"},{"issue":"12","key":"e_1_2_12_34_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0115936","article-title":"Involvement of miR\u2010518c\u20105p to Growth and Metastasis in Oral Cancer","volume":"9","author":"Kinouchi M.","year":"2014","journal-title":"PLoS One"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70110","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mc.70110","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:09:30Z","timestamp":1790532570000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.70110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":33,"alternative-id":["10.1002\/mc.70110"],"URL":"https:\/\/doi.org\/10.1002\/mc.70110","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]},"assertion":[{"value":"2025-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"mc.70110"}}