{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:56:05Z","timestamp":1794012965026,"version":"4.8.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Natura Science Foundatin of Guangxi Zhuang Autonomous Region","award":["2024JJB140740"],"award-info":[{"award-number":["2024JJB140740"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Rev and Rep"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1007\/s12015-026-11158-w","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T08:09:36Z","timestamp":1781770176000},"page":"2919-2937","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ANXA3 activates HIF-1\u03b1\/VEGF Signaling Via the PI3K\/AKT\/mTOR Pathway to Promote Osteosarcoma Stem Cell-Like Phenotype"],"prefix":"10.1007","volume":"22","author":[{"given":"Shengtao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"11158_CR1","doi-asserted-by":"crossref","unstructured":"Isakoff, M. S., Bielack, S. S., Meltzer, P., & Gorlick, R. (2015). Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. Journal of Clinical Oncology [Internet] ;33:3029\u201335. Available from: https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4979196\/","DOI":"10.1200\/JCO.2014.59.4895"},{"key":"11158_CR2","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41571-021-00519-8","volume":"18","author":"J Gill","year":"2021","unstructured":"Gill, J., & Gorlick, R. (2021). Advancing therapy for osteosarcoma. Nature Reviews Clinical Oncology, 18, 609\u2013624.","journal-title":"Nature Reviews Clinical Oncology"},{"key":"11158_CR3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/14737140.2018.1413939","volume":"18","author":"DJ Harrison","year":"2017","unstructured":"Harrison, D. J., Geller, D. S., Gill, J. D., Lewis, V. O., & Gorlick, R. (2017). Current and future therapeutic approaches for osteosarcoma. Expert Review of Anticancer Therapy, 18, 39\u201350.","journal-title":"Expert Review of Anticancer Therapy"},{"key":"11158_CR4","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.3892\/ol.2014.1935","volume":"7","author":"H HE","year":"2014","unstructured":"HE, H., NI, J., & HUANG, J. (2014). Molecular mechanisms of chemoresistance in osteosarcoma (Review). Oncology Letters, 7, 1352\u20131362.","journal-title":"Oncology Letters"},{"key":"11158_CR5","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.pbiomolbio.2025.07.001","volume":"197","author":"X Wang","year":"2025","unstructured":"Wang, X., Zhu, K., Hu, J., & Zhang, C. (2025). Advances and challenges in the treatment of osteosarcoma. Progress in Biophysics and Molecular Biology, 197, 60\u201374.","journal-title":"Progress in Biophysics and Molecular Biology"},{"key":"11158_CR6","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/35102167","volume":"414","author":"T Reya","year":"2001","unstructured":"Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105\u2013111.","journal-title":"Nature"},{"key":"11158_CR7","doi-asserted-by":"crossref","unstructured":"Nassar, D., & Blanpain, C. (2016). Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Annual Review of Pathology: Mechanisms of Disease [Internet] ;11:47\u201376. Available from: http:\/\/blanpainlab.ulb.ac.be\/images\/pdf\/annurev-pathol-012615-044438.pdf","DOI":"10.1146\/annurev-pathol-012615-044438"},{"key":"11158_CR8","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1038\/nm.4409","volume":"23","author":"E Batlle","year":"2017","unstructured":"Batlle, E., & Clevers, H. (2017). Cancer stem cells revisited. Nature medicine, 23, 1124\u20131134.","journal-title":"Nature medicine"},{"key":"11158_CR9","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.canlet.2015.11.003","volume":"370","author":"G-N Yan","year":"2016","unstructured":"Yan, G-N., Lv, Y-F., & Guo, Q-N. (2016). Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets. Cancer Letters, 370, 268\u2013274.","journal-title":"Cancer Letters"},{"key":"11158_CR10","doi-asserted-by":"crossref","unstructured":"Gupta, P. B., Chaffer, C. L., & Weinberg, R. A. Cancer stem cells: mirage or reality? Nature medicine [Internet] 2009 [cited 2019 Jun 26];15:1010\u20132. Available from: https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19734877","DOI":"10.1038\/nm0909-1010"},{"key":"11158_CR11","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1593\/neo.05394","volume":"7","author":"CP Gibbs","year":"2005","unstructured":"Gibbs, C. P., Kukekov, V. G., Reith, J. D., Tchigrinova, O., Suslov, O. N., Scott, E. W., Ghivizzani, S. C., Ignatova, T. N., & Steindler, D. A. (2005). Stem-Like Cells in Bone Sarcomas: Implications for Tumorigenesis. Neoplasia (New York, N.Y.), 7, 967\u2013976.","journal-title":"Neoplasia (New York, N.Y.)"},{"key":"11158_CR12","doi-asserted-by":"crossref","unstructured":"Chen, R-L., Wang, G., Zheng, Y., Hua, Y., & Cai, Z. (2019). Drug resistance-related microRNAs in osteosarcoma: Translating basic evidence into therapeutic strategies. Journal of Cellular and Molecular Medicine, 23, 2280\u20132292.","DOI":"10.1111\/jcmm.14064"},{"key":"11158_CR13","doi-asserted-by":"crossref","unstructured":"Guo, C., Li, N., Dong, C., Wang, L., Li, Z., Liu, Q., Ma, Q., Greenaway, F. T., Tian, Y., Hao, L., Liu, S., & Sun, M-Z. (2020). 33-kDa ANXA3 isoform contributes to hepatocarcinogenesis via modulating ERK, PI3K\/Akt-HIF and intrinsic apoptosis pathways. Journal of Advanced Research [Internet] ;30:85\u2013102. Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S2090123220302307?via%3Dihub","DOI":"10.1016\/j.jare.2020.11.003"},{"key":"11158_CR14","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/mc.22126","volume":"54","author":"Q-Z Pan","year":"2013","unstructured":"Pan, Q-Z., Pan, K., Weng, D-S., Zhao, J-J., Zhang, X-F., Wang, D-D., Lv, L., Jiang, S-S., Zheng, H-X., & Xia, J-C. (2013). Annexin A3 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma. Molecular Carcinogenesis, 54, 598\u2013607.","journal-title":"Molecular Carcinogenesis"},{"key":"11158_CR15","doi-asserted-by":"crossref","unstructured":"Xu, B., Zhang, X., Gao, Y., Song, J., & Shi, B. (2020). Microglial Annexin A3 promoted the development of melanoma via activation of hypoxia-inducible factor\u20101\u03b1\/vascular endothelial growth factor signaling pathway. Journal of Clinical Laboratory Analysis, 35(2), e23622.","DOI":"10.1002\/jcla.23622"},{"key":"11158_CR16","doi-asserted-by":"crossref","unstructured":"Zeng, X., Wang, S., Gui, P., Wu, H., & Li, Z. (2019). Expression and significance of Annexin A3 in the osteosarcoma cell lines HOS and U2OS. Molecular Medicine Reports, 20(3), 2583\u20132590.","DOI":"10.3892\/mmr.2019.10513"},{"key":"11158_CR17","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","volume":"176","author":"RS Apte","year":"2019","unstructured":"Apte, R. S., Chen, D. S., & Ferrara, N. (2019). VEGF in Signaling and Disease: Beyond Discovery and Development. Cell, 176, 1248\u20131264.","journal-title":"Cell"},{"key":"11158_CR18","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1007\/s13577-018-0224-z","volume":"32","author":"S Lin","year":"2018","unstructured":"Lin, S., Zhu, B., Huang, G., Zeng, Q., & Wang, C. (2018). Microvesicles derived from human bone marrow mesenchymal stem cells promote U2OS cell growth under hypoxia: the role of PI3K\/AKT and HIF-1\u03b1. Human Cell, 32, 64\u201374.","journal-title":"Human Cell"},{"key":"11158_CR19","doi-asserted-by":"crossref","unstructured":"Mimeault, M., & Batra, S. K. (2013). Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine [Internet] ;17:30\u201354. Available from: https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3560853\/","DOI":"10.1111\/jcmm.12004"},{"key":"11158_CR20","doi-asserted-by":"crossref","unstructured":"Yeh, Y-H., Hsiao, H-F., Yeh, Y-C., Chen, T-W., & Li, T-K. (2018). Inflammatory interferon activates HIF-1\u03b1-mediated epithelial-to-mesenchymal transition via PI3K\/AKT\/mTOR pathway. Journal of Experimental & Clinical Cancer Research, 37(1), 70.","DOI":"10.1186\/s13046-018-0730-6"},{"key":"11158_CR21","doi-asserted-by":"publisher","first-page":"5667","DOI":"10.3390\/cancers13225667","volume":"13","author":"MJ Jo","year":"2021","unstructured":"Jo, M. J., Kim, B. G., Kim, W. Y., Lee, D-H., Yun, H. K., Jeong, S., Park, S. H., Kim, B. R., Kim, J. L., Kim, D. Y., Lee, S. I., & Oh, S. C. (2021). Cannabidiol Suppresses Angiogenesis and Stemness of Breast Cancer Cells by Downregulation of Hypoxia-Inducible Factors-1\u03b1. Cancers, 13, 5667.","journal-title":"Cancers"},{"key":"11158_CR22","doi-asserted-by":"crossref","unstructured":"Chu, X., Tian, W., Ning, J., Xiao, G., Zhou, Y., Wang, Z., Zhai, Z., Tanzhu, G., Yang, J., & Zhou, R. (2024). Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduction and Targeted Therapy [Internet] ;9:170. Available from: https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC11224386\/","DOI":"10.1038\/s41392-024-01851-y"},{"key":"11158_CR23","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.anireprosci.2011.03.002","volume":"125","author":"Z Zhang","year":"2011","unstructured":"Zhang, Z., Yu, D., Yin, D., & Wang, Z. (2011). Activation of PI3K\/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells. Animal Reproduction Science, 125, 42\u201348.","journal-title":"Animal Reproduction Science"},{"key":"11158_CR24","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1152\/physrev.00030.2001","volume":"82","author":"V Gerke","year":"2002","unstructured":"Gerke, V., Moss, S. E., & Annexins (2002). From Structure to Function. Physiological Reviews, 82, 331\u2013371.","journal-title":"Physiological Reviews"},{"key":"11158_CR25","doi-asserted-by":"crossref","unstructured":"Rescher, U. (2004). Annexins - unique membrane binding proteins with diverse functions. Journal of Cell Science [Internet] ;117:2631\u20139. Available from: https:\/\/jcs.biologists.org\/content\/117\/13\/2631","DOI":"10.1242\/jcs.01245"},{"key":"11158_CR26","doi-asserted-by":"crossref","unstructured":"Yin, J., Yan, X., Yao, X., Zhang, Y., Shan, Y., Mao, N., Yang, Y., & Pan, L. (2011). Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients. Journal of Cellular and Molecular Medicine [Internet] [cited 2025 Oct 23];16:337\u201348. Available from: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC3823297\/","DOI":"10.1111\/j.1582-4934.2011.01316.x"},{"key":"11158_CR27","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1016\/j.eururo.2008.01.001","volume":"54","author":"T Jens K\u00f6llermann","year":"2008","unstructured":"Jens K\u00f6llermann, T., Schlomm, Bang, H., Schwall, G. P., von Christoph, R., Schostak, M., Hartwig Huland, Berg, W., Sauter, G., & Klocker, H. (2008). Andr\u00e9 Schrattenholz. Expression and Prognostic Relevance of Annexin A3 in Prostate Cancer. European Urology, 54, 1314\u20131323.","journal-title":"European Urology"},{"key":"11158_CR28","doi-asserted-by":"publisher","unstructured":"Jeun, M., Park, S., Kim, Y., Choi, J., Song, S. H., Jeong, I. G., Kim, C., & Lee, K. H. (2017). Self\u2010normalized detection of ANXA3 from untreated urine of prostate cancer patients without digital rectal examination. Advanced Healthcare Materials, 6(17). https:\/\/doi.org\/10.1002\/adhm.201700449","DOI":"10.1002\/adhm.201700449"},{"key":"11158_CR29","unstructured":"Phei Er Saw, Liu, Q., Wong, P-P., & Song, E. (2024). Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell stem cell [Internet] ;Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/38925125\/"},{"key":"11158_CR30","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.stemcr.2015.05.013","volume":"5","author":"M Tong","year":"2015","unstructured":"Tong, M., Fung, T-M., Luk, S., Ng, K-Y., Lee, T., Lin, C-H., Yam, J., Chan, K., Ng, F., Zheng, B-J., Yuan, Y-F., Xie, D., et al. (2015). ANXA3\/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma. Stem Cell Reports, 5, 45\u201359.","journal-title":"Stem Cell Reports"},{"key":"11158_CR31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/sj.cr.7310118","volume":"17","author":"F Li","year":"2006","unstructured":"Li, F., Tiede, B., Massagu\u00e9, J., & Kang, Y. (2006). Beyond tumorigenesis: cancer stem cells in metastasis. Cell Research, 17, 3\u201314.","journal-title":"Cell Research"},{"key":"11158_CR32","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nrc1590","volume":"5","author":"M Dean","year":"2005","unstructured":"Dean, M., Fojo, T., & Bates, S. (2005). Tumour stem cells and drug resistance. Nature Reviews Cancer, 5, 275\u2013284.","journal-title":"Nature Reviews Cancer"},{"key":"11158_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41392-022-01080-1","volume":"7","author":"Z Luo","year":"2022","unstructured":"Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022). Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduction and Targeted Therapy, 7, 1\u201330.","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"11158_CR34","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","volume":"148","author":"L Semenza Gregg","year":"2012","unstructured":"Semenza Gregg, L. (2012). Hypoxia-Inducible Factors in Physiology and Medicine. Cell, 148, 399\u2013408.","journal-title":"Cell"},{"key":"11158_CR35","first-page":"34","volume":"14","author":"R Ravi","year":"2000","unstructured":"Ravi, R., Bijoyesh Mookerjee, Bhujwalla, Z. M., Sutter, C. H., Dmitri Artemov, Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. PubMed, 14, 34\u201344.","journal-title":"PubMed"},{"key":"11158_CR36","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","volume":"169","author":"BD Manning","year":"2017","unstructured":"Manning, B. D., & Toker, A. (2017). AKT\/PKB Signaling: Navigating the Network. Cell, 169, 381\u2013405.","journal-title":"Cell"},{"key":"11158_CR37","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1101\/gad.1212704","volume":"18","author":"N Hay","year":"2004","unstructured":"Hay, N. (2004). Upstream and downstream of mTOR. Genes & Development, 18, 1926\u20131945.","journal-title":"Genes & Development"},{"key":"11158_CR38","doi-asserted-by":"publisher","first-page":"32116","DOI":"10.1074\/jbc.M110.131284","volume":"285","author":"YK Choi","year":"2010","unstructured":"Choi, Y. K., Kim, C-K., Lee, H., Jeoung, D., Ha, K-S., Kwon, Y-G., Kim, K-W., & Kim, Y-M. (2010). Carbon Monoxide Promotes VEGF Expression by Increasing HIF-1\u03b1 Protein Level via Two Distinct Mechanisms, Translational Activation and Stabilization of HIF-1\u03b1 Protein. Journal of Biological Chemistry, 285, 32116\u201332125.","journal-title":"Journal of Biological Chemistry"}],"container-title":["Stem Cell Reviews and Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12015-026-11158-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12015-026-11158-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12015-026-11158-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T07:27:42Z","timestamp":1783668462000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12015-026-11158-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["11158"],"URL":"https:\/\/doi.org\/10.1007\/s12015-026-11158-w","relation":{},"ISSN":["2629-3269","2629-3277"],"issn-type":[{"value":"2629-3269","type":"print"},{"value":"2629-3277","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"16 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent for publication was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"All experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee of Nanxishan Hospital of Guangxi Zhuang Autonomous Region (NXSYY-202402) and carried out in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Number"}}]}}