{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:38:27Z","timestamp":1791650307349,"version":"4.3.4"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81272828"],"award-info":[{"award-number":["81272828"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ningbo Clinical Research Center for Urological Disease"},{"DOI":"10.13039\/100007834","name":"Natural Science Foundation of Ningbo","doi-asserted-by":"publisher","award":["2023J158"],"award-info":[{"award-number":["2023J158"]}],"id":[{"id":"10.13039\/100007834","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The RON receptor tyrosine kinase is critical in the pathogenesis of various cancer types, however, its role in bladder cancer invasive growth is still largely unknown. Here, we found that over 90% of bladder cancer samples exhibit elevated levels of RON expression, with significantly higher expression levels observed in invasive bladder cancer compared to non-invasive bladder cancer. In vitro, RON activation resulted in increased bladder cancer cell migration and invasiveness. Results from mRNA sequencing and transcriptome analysis further demonstrated that MMP12, a downstream molecule of RON, is functionally involved in regulating RON-mediated bladder cancer cell migration and invasiveness. The underlying mechanism appeared to be the RON-mediated inhibition of HIF-2\u03b1 ubiquitination, which is channeled through the activation of the JNK signaling pathway. Consequently, the activated JNK pathway increased MMP12 expression, ultimately driving bladder cancer cell migration and invasion. As evident in bioinformatics and dual-luciferase reporter assays, the RON mRNA at its 3\u2032-untranslated regions specifically interacted with hsa-miR-659-3p. The binding of hsa-miR-659-3p downregulated the RON gene expression, attenuating the receptor-mediated tumorigenic activities of bladder cancer cells in vitro and in vivo. In conclusion, aberrant RON expression in bladder cancer cells and MMP12 and HIF-2\u03b1 activities form a functional axis that causes increased bladder cancer cell migration and invasion. The fact that hsa-miR-659-3p downregulates RON expression indicates its critical role in attenuating RON-mediated tumorigenic effect on bladder cancer cells. These findings highlight the importance of RON targeting as a therapeutic means for potential bladder cancer therapy.<\/jats:p>","DOI":"10.1038\/s41419-024-07245-w","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T22:44:48Z","timestamp":1731969888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["RON receptor tyrosine kinase as a critical determinant in promoting tumorigenic behaviors of bladder cancer cells through regulating MMP12 and HIF-2\u03b1 pathways"],"prefix":"10.1038","volume":"15","author":[{"given":"Ke-jie","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha-zhou","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-long","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-yun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-yu","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-jie","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5350-0362","authenticated-orcid":false,"given":"Qi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"7245_CR1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.eururo.2016.06.010","volume":"71","author":"S Antoni","year":"2017","unstructured":"Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96\u2013108.","journal-title":"Eur Urol"},{"key":"7245_CR2","doi-asserted-by":"publisher","first-page":"S33","DOI":"10.1038\/551S33a","volume":"551","author":"M Grayson","year":"2017","unstructured":"Grayson M. Bladder cancer. Nature. 2017;551:S33.","journal-title":"Nature"},{"key":"7245_CR3","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.1001\/jama.2020.17598","volume":"324","author":"AT Lenis","year":"2020","unstructured":"Lenis AT, Lec PM, Chamie K, Mshs MD. Bladder cancer: a review. J Am Med Assoc. 2020;324:1980\u201391.","journal-title":"J Am Med Assoc"},{"key":"7245_CR4","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.eururo.2011.03.023","volume":"59","author":"A Stenzl","year":"2011","unstructured":"Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol. 2011;59:1009\u201318.","journal-title":"Eur Urol"},{"key":"7245_CR5","doi-asserted-by":"publisher","first-page":"404","DOI":"10.3322\/caac.21631","volume":"70","author":"VG Patel","year":"2020","unstructured":"Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70:404\u201323.","journal-title":"CA Cancer J Clin"},{"key":"7245_CR6","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1038\/nrc3545","volume":"13","author":"H-P Yao","year":"2013","unstructured":"Yao H-P, Zhou Y-Q, Zhang R, Wang M-H. MSP-RON signaling in cancer: pathogenesis and therapeutic potential. Nat Rev Cancer. 2013;13:466\u201381.","journal-title":"Nat Rev Cancer"},{"key":"7245_CR7","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1038\/aps.2010.106","volume":"31","author":"M-H Wang","year":"2010","unstructured":"Wang M-H, Padhye SS, Guin S, Ma Q, Zhou Y. Potential therapeutics specific to c-MET\/RON receptor tyrosine kinases for molecular targeting in cancer therapy. Acta Pharm Sin. 2010;31:1181\u20138.","journal-title":"Acta Pharm Sin"},{"key":"7245_CR8","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1016\/j.juro.2006.07.048","volume":"176","author":"P-Y Hsu","year":"2006","unstructured":"Hsu P-Y, Liu H-S, Cheng H-L, Tzai T-S, Guo H-R, Ho C-L, et al. Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol. 2006;176:2262\u20137.","journal-title":"J Urol"},{"key":"7245_CR9","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1002\/path.2245","volume":"213","author":"M-H Wang","year":"2007","unstructured":"Wang M-H, Lee W, Luo Y-L, Weis MT, Yao H-P. Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumourigenic phenotypes in thyroid cancer cells. J Pathol. 2007;213:402\u201311.","journal-title":"J Pathol"},{"key":"7245_CR10","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1038\/sj.bjc.6602593","volume":"92","author":"H-L Cheng","year":"2005","unstructured":"Cheng H-L, Liu H-S, Lin Y-J, Chen HH-W, Hsu P-Y, Chang T-Y, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005;92:1906\u201314.","journal-title":"Br J Cancer"},{"key":"7245_CR11","first-page":"6547","volume":"15","author":"J-F Chen","year":"2018","unstructured":"Chen J-F, Yu B-X, Ma L, Lv X-Y, Jiang J-H, Ma Q. RON is overexpressed in bladder cancer and contributes to tumorigenic phenotypes in 5637 cells. Oncol Lett. 2018;15:6547\u201354.","journal-title":"Oncol Lett"},{"key":"7245_CR12","doi-asserted-by":"publisher","first-page":"7093","DOI":"10.18632\/aging.204279","volume":"14","author":"J Chen","year":"2022","unstructured":"Chen J, Wang K, Ye S, Meng X, Jia X, Huang Y, et al. Tyrosine kinase receptor RON activates the MAPK\/RSK\/CREB signal pathway to enhance CXCR4 expression and promote cell migration and invasion in bladder cancer. Aging (Albany NY). 2022;14:7093\u2013108.","journal-title":"Aging (Albany NY)"},{"key":"7245_CR13","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1016\/j.jtcvs.2017.11.110","volume":"155","author":"E Ella","year":"2018","unstructured":"Ella E, Harel Y, Abraham M, Wald H, Benny O, Karsch-Bluman A, et al. Matrix metalloproteinase 12 promotes tumor propagation in the lung. J Thorac Cardiovasc Surg. 2018;155:2164\u2013.e1.","journal-title":"J Thorac Cardiovasc Surg"},{"key":"7245_CR14","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.ejcb.2015.10.004","volume":"94","author":"AR Highet","year":"2015","unstructured":"Highet AR, Khoda SM, Buckberry S, Leemaqz S, Bianco-Miotto T, Harrington E, et al. Hypoxia-induced HIF-1\/HIF-2 activity alters trophoblast transcriptional regulation and promotes invasion. Eur J Cell Biol. 2015;94:589\u2013602.","journal-title":"Eur J Cell Biol"},{"key":"7245_CR15","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.molmed.2014.06.005","volume":"20","author":"J Hayes","year":"2014","unstructured":"Hayes J, Peruzzi PP, Lawler S. MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med. 2014;20:460\u20139.","journal-title":"Trends Mol Med"},{"key":"7245_CR16","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.3390\/cancers14082037","volume":"14","author":"A Cazes","year":"2022","unstructured":"Cazes A, Childers BG, Esparza E, Lowy AM. The MST1R\/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies. Cancers (Basel). 2022;14:2037.","journal-title":"Cancers (Basel)"},{"key":"7245_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03729-1","volume":"12","author":"C-L Lin","year":"2021","unstructured":"Lin C-L, Ying T-H, Yang S-F, Chiou H-L, Chen Y-S, Kao S-H, et al. MTA2 silencing attenuates the metastatic potential of cervical cancer cells by inhibiting AP1-mediated MMP12 expression via the ASK1\/MEK3\/p38\/YB1 axis. Cell Death Dis. 2021;12:451.","journal-title":"Cell Death Dis"},{"key":"7245_CR18","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1007\/s13402-021-00620-1","volume":"44","author":"W-Y Hung","year":"2021","unstructured":"Hung W-Y, Lee W-J, Cheng G-Z, Tsai C-H, Yang Y-C, Lai T-C, et al. Blocking MMP-12-modulated epithelial-mesenchymal transition by repurposing penfluridol restrains lung adenocarcinoma metastasis via uPA\/uPAR\/TGF-\u03b2\/Akt pathway. Cell Oncol (Dordr). 2021;44:1087\u2013103.","journal-title":"Cell Oncol (Dordr)"},{"key":"7245_CR19","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/nrm3758","volume":"15","author":"S Lamouille","year":"2014","unstructured":"Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178\u201396.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"7245_CR20","first-page":"471","volume":"8","author":"T Onita","year":"2002","unstructured":"Onita T, Ji PG, Xuan JW, Sakai H, Kanetake H, Maxwell PH, et al. Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1\/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clin Cancer Res. 2002;8:471\u201380.","journal-title":"Clin Cancer Res"},{"key":"7245_CR21","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/fcell.2016.00011","volume":"4","author":"T Kietzmann","year":"2016","unstructured":"Kietzmann T, Mennerich D, Dimova EY. Hypoxia-inducible factors (HIFs) and phosphorylation: impact on stability, localization, and transactivity. Front Cell Dev Biol. 2016;4:11.","journal-title":"Front Cell Dev Biol"},{"key":"7245_CR22","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.taap.2012.11.014","volume":"266","author":"Y Xu","year":"2013","unstructured":"Xu Y, Li Y, Li H, Pang Y, Zhao Y, Jiang R, et al. The accumulations of HIF-1\u03b1 and HIF-2\u03b1 by JNK and ERK are involved in biphasic effects induced by different levels of arsenite in human bronchial epithelial cells. Toxicol Appl Pharm. 2013;266:187\u201397.","journal-title":"Toxicol Appl Pharm"},{"key":"7245_CR23","doi-asserted-by":"publisher","first-page":"721","DOI":"10.3892\/or.2017.5356","volume":"37","author":"J-F Chen","year":"2017","unstructured":"Chen J-F, Yu B-X, Yu R, Ma L, Lv X-Y, Cheng Y, et al. Monoclonal antibody Zt\/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1\/S arrest and apoptosis. Oncol Rep. 2017;37:721\u20138.","journal-title":"Oncol Rep"},{"key":"7245_CR24","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s10555-006-7886-9","volume":"25","author":"EI Deryugina","year":"2006","unstructured":"Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006;25:9\u201334.","journal-title":"Cancer Metastasis Rev"},{"key":"7245_CR25","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1152\/physrev.00024.2002","volume":"83","author":"M Mareel","year":"2003","unstructured":"Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev. 2003;83:337\u201376.","journal-title":"Physiol Rev"},{"key":"7245_CR26","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1158\/1078-0432.1086.11.3","volume":"11","author":"H-S Hofmann","year":"2005","unstructured":"Hofmann H-S, Hansen G, Richter G, Taege C, Simm A, Silber R-E, et al. Matrix metalloproteinase-12 expression correlates with local recurrence and metastatic disease in non-small cell lung cancer patients. Clin Cancer Res. 2005;11:1086\u201392.","journal-title":"Clin Cancer Res"},{"key":"7245_CR27","doi-asserted-by":"publisher","unstructured":"Ng KT, Qi X, Kong KL, Cheung BY, Lo CM, Poon RT, et al. Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with poor prognosis of hepatocellular carcinoma. Eur. J. Cancer. 2011;47. https:\/\/doi.org\/10.1016\/j.ejca.2011.05.032.","DOI":"10.1016\/j.ejca.2011.05.032"},{"key":"7245_CR28","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1034\/j.1600-0625.2003.120201.x","volume":"12","author":"E Kerkel\u00e4","year":"2003","unstructured":"Kerkel\u00e4 E, Saarialho-Kere U. Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol. 2003;12:109\u201325.","journal-title":"Exp Dermatol"},{"key":"7245_CR29","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1158\/2326-6066.CIR-16-0259","volume":"5","author":"Q Zhou","year":"2017","unstructured":"Zhou Q, Xian M, Xiang S, Xiang D, Shao X, Wang J, et al. All-trans retinoic acid prevents osteosarcoma metastasis by inhibiting M2 polarization of tumor-associated macrophages. Cancer Immunol Res. 2017;5:547\u201359.","journal-title":"Cancer Immunol Res"},{"key":"7245_CR30","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.1158\/1078-0432.CCR-06-1187","volume":"13","author":"AK Kader","year":"2007","unstructured":"Kader AK, Liu J, Shao L, Dinney CP, Lin J, Wang Y, et al. Matrix metalloproteinase polymorphisms are associated with bladder cancer invasiveness. Clin Cancer Res. 2007;13:2614\u201320.","journal-title":"Clin Cancer Res"},{"key":"7245_CR31","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1126\/science.aaf4405","volume":"352","author":"EB Rankin","year":"2016","unstructured":"Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science. 2016;352:175\u201380.","journal-title":"Science"},{"key":"7245_CR32","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.pathol.4.110807.092222","volume":"4","author":"YS Lee","year":"2009","unstructured":"Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009;4:199\u2013227.","journal-title":"Annu Rev Pathol"},{"key":"7245_CR33","unstructured":"Li S, Fang Y, Qin H, Fu W, Zhang X. miR-659-3p is involved in the regulation of the chemotherapy response of colorectal cancer via modulating the expression of SPHK1. Am J Cancer Res. 2016;6:1976\u201385."},{"key":"7245_CR34","first-page":"2470","volume":"11","author":"Z Liu","year":"2018","unstructured":"Liu Z, He C, Qu Y, Chen X, Zhu H, Xiang B. MiR-659-3p regulates the progression of chronic myeloid leukemia by targeting SPHK1. Int J Clin Exp Pathol. 2018;11:2470\u20138.","journal-title":"Int J Clin Exp Pathol"},{"key":"7245_CR35","doi-asserted-by":"publisher","first-page":"13295","DOI":"10.18632\/oncotarget.3745","volume":"6","author":"S Stigliani","year":"2015","unstructured":"Stigliani S, Scaruffi P, Lagazio C, Persico L, Carlini B, Varesio L, et al. Deregulation of focal adhesion pathway mediated by miR-659-3p is implicated in bone marrow infiltration of stage M neuroblastoma patients. Oncotarget. 2015;6:13295\u2013308.","journal-title":"Oncotarget"},{"key":"7245_CR36","first-page":"1286","volume":"11","author":"X-Y Meng","year":"2021","unstructured":"Meng X-Y, Zhang H-Z, Ren Y-Y, Wang K-J, Chen J-F, Su R, et al. Pinin promotes tumor progression via activating CREB through PI3K\/AKT and ERK\/MAPK pathway in prostate cancer. Am J Cancer Res. 2021;11:1286\u2013303.","journal-title":"Am J Cancer Res"},{"key":"7245_CR37","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s13046-022-02404-3","volume":"41","author":"L Chen","year":"2022","unstructured":"Chen L, Song Y, Hou T, Li X, Cheng L, Li Y, et al. Circ_0004087 interaction with SND1 promotes docetaxel resistance in prostate cancer by boosting the mitosis error correction mechanism. J Exp Clin Cancer Res. 2022;41:194.","journal-title":"J Exp Clin Cancer Res"},{"key":"7245_CR38","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.3389\/fonc.2020.01720","volume":"10","author":"K-J Wang","year":"2020","unstructured":"Wang K-J, Wang K-Y, Zhang H-Z, Meng X-Y, Chen J-F, Wang P, et al. Up-regulation of RIP3 alleviates prostate cancer progression by activation of RIP3\/MLKL signaling pathway and induction of necroptosis. Front Oncol. 2020;10:1720.","journal-title":"Front Oncol"},{"key":"7245_CR39","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.canlet.2020.03.004","volume":"478","author":"X Wu","year":"2020","unstructured":"Wu X, Zhou Z, Xu S, Liao C, Chen X, Li B, et al. Extracellular vesicle packaged LMP1-activated fibroblasts promote tumor progression via autophagy and stroma-tumor metabolism coupling. Cancer Lett. 2020;478:93\u2013106.","journal-title":"Cancer Lett"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07245-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07245-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07245-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T11:14:36Z","timestamp":1732014876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-07245-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["7245"],"URL":"https:\/\/doi.org\/10.1038\/s41419-024-07245-w","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]},"assertion":[{"value":"8 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study involving humans was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all the subjects. Ethics approval for human subjects was provided by the Ethical Committee of the First Affiliated Hospital of Ningbo University, with the approval number: 2022-065A. All animal experiments complied with the National Research Council\u2019s Guide for the Care and Use of Laboratory Animals. Ethics approval for animal work was provided by the Institutional Animal Care and Use Committee (IACUC), ZJCLA, with the approval number: ZJCLA-IACUC-20010178.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors agree to the content of the manuscript and to publish the paper as co-authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"844"}}