{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:49:30Z","timestamp":1790952570413,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81830082"],"award-info":[{"award-number":["81830082"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82030078"],"award-info":[{"award-number":["82030078"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82003128"],"award-info":[{"award-number":["82003128"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"natural science foundation of china","doi-asserted-by":"crossref","award":["82072609"],"award-info":[{"award-number":["82072609"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"natural science foundation of china","doi-asserted-by":"crossref","award":["81621004"],"award-info":[{"award-number":["81621004"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangzhou Science and Technology Plan Projects","award":["201803010098"],"award-info":[{"award-number":["201803010098"]}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2018B030311009"],"award-info":[{"award-number":["2018B030311009"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2016A030308002"],"award-info":[{"award-number":["2016A030308002"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2018B030311060"],"award-info":[{"award-number":["2018B030311060"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2019A1515110118"],"award-info":[{"award-number":["2019A1515110118"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Cancer"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-\u03baB\/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-\u03baB pathway via promoting IKK\u03b2-mediated I\u03baB\u03b1 phosphorylation, inhibiting I\u03baB\u03b1 feedback loop and facilitating NF-\u03baB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We revealed a plausible mechanism for circIKBKB-mediated NF-\u03baB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-021-01394-8","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T02:02:58Z","timestamp":1627524178000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-\u03baB\/bone remodeling factors signaling"],"prefix":"10.1186","volume":"20","author":[{"given":"Yingru","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xincheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meisongzhu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoling","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yameng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libing","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0572-1344","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"1394_CR1","doi-asserted-by":"publisher","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021. https:\/\/doi.org\/10.3322\/caac.21660.","DOI":"10.3322\/caac.21660"},{"key":"1394_CR2","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nrc1670","volume":"5","author":"B Weigelt","year":"2005","unstructured":"Weigelt B, Peterse JL, Van\u2019t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591\u2013602. https:\/\/doi.org\/10.1038\/nrc1670.","journal-title":"Nat Rev Cancer"},{"key":"1394_CR3","doi-asserted-by":"publisher","first-page":"4951","DOI":"10.1158\/0008-5472.CAN-09-0099","volume":"69","author":"J Lu","year":"2009","unstructured":"Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, Cristofanilli M, Dontu G, Bidaut L, Valero V, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951\u20133. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-0099.","journal-title":"Cancer Res"},{"key":"1394_CR4","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nrc3055","volume":"11","author":"KN Weilbaecher","year":"2011","unstructured":"Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11:411\u201325. https:\/\/doi.org\/10.1038\/nrc3055.","journal-title":"Nat Rev Cancer"},{"key":"1394_CR5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4161\/cbt.7.1.5163","volume":"7","author":"M Akhtari","year":"2008","unstructured":"Akhtari M, Mansuri J, Newman KA, Guise TM, Seth P. Biology of breast cancer bone metastasis. Cancer Biol Ther. 2008;7:3\u20139. https:\/\/doi.org\/10.4161\/cbt.7.1.5163.","journal-title":"Cancer Biol Ther"},{"key":"1394_CR6","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/nrc867","volume":"2","author":"GR Mundy","year":"2002","unstructured":"Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584\u201393. https:\/\/doi.org\/10.1038\/nrc867.","journal-title":"Nat Rev Cancer"},{"key":"1394_CR7","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1023\/a:1019905111666","volume":"75","author":"T Michigami","year":"2002","unstructured":"Michigami T, Hiraga T, Williams PJ, Niewolna M, Nishimura R, Mundy GR, Yoneda T. The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat. 2002;75:249\u201358. https:\/\/doi.org\/10.1023\/a:1019905111666.","journal-title":"Breast Cancer Res Treat"},{"key":"1394_CR8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jpor.2014.08.001","volume":"59","author":"K Niibe","year":"2015","unstructured":"Niibe K, Ouchi T, Iwasaki R, Nakagawa T, Horie N. Osteonecrosis of the jaw in patients with dental prostheses being treated with bisphosphonates or denosumab. J Prosthodont Res. 2015;59:3\u20135. https:\/\/doi.org\/10.1016\/j.jpor.2014.08.001.","journal-title":"J Prosthodont Res"},{"key":"1394_CR9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41572-020-00216-3","volume":"6","author":"RE Coleman","year":"2020","unstructured":"Coleman RE, Croucher PI, Padhani AR, Clezardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L. Bone metastases. Nat Rev Dis Primers. 2020;6:83. https:\/\/doi.org\/10.1038\/s41572-020-00216-3.","journal-title":"Nat Rev Dis Primers"},{"key":"1394_CR10","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.cell.2012.10.005","volume":"151","author":"B Ell","year":"2012","unstructured":"Ell B, Kang Y. SnapShot: bone metastasis. Cell. 2012;151:690. https:\/\/doi.org\/10.1016\/j.cell.2012.10.005.","journal-title":"Cell"},{"key":"1394_CR11","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.7150\/thno.45351","volume":"11","author":"X Yuan","year":"2021","unstructured":"Yuan X, Qian N, Ling S, Li Y, Sun W, Li J, Du R, Zhong G, Liu C, Yu G, et al. Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells. Theranostics. 2021;11:1429\u201345. https:\/\/doi.org\/10.7150\/thno.45351.","journal-title":"Theranostics"},{"issue":"10","key":"1394_CR12","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.3390\/ijms17101764","volume":"17","author":"CS Shemanko","year":"2016","unstructured":"Shemanko CS, Cong Y, Forsyth A. What is breast in the bone? Int J Mol Sci. 2016;17(10):1764. https:\/\/doi.org\/10.3390\/ijms17101764.","journal-title":"Int J Mol Sci"},{"key":"1394_CR13","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/s10911-005-5399-8","volume":"10","author":"W Kozlow","year":"2005","unstructured":"Kozlow W, Guise TA. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J Mammary Gland Biol Neoplasia. 2005;10:169\u201380. https:\/\/doi.org\/10.1007\/s10911-005-5399-8.","journal-title":"J Mammary Gland Biol Neoplasia"},{"key":"1394_CR14","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13046-018-1001-2","volume":"38","author":"M Infante","year":"2019","unstructured":"Infante M, Fabi A, Cognetti F, Gorini S, Caprio M, Fabbri A. RANKL\/RANK\/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives. J Exp Clin Cancer Res. 2019;38:12. https:\/\/doi.org\/10.1186\/s13046-018-1001-2.","journal-title":"J Exp Clin Cancer Res"},{"key":"1394_CR15","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1158\/1055-9965.EPI-12-1318-T","volume":"22","author":"CL Washam","year":"2013","unstructured":"Washam CL, Byrum SD, Leitzel K, Ali SM, Tackett AJ, Gaddy D, Sundermann SE, Lipton A, Suva LJ. Identification of PTHrP(12\u201348) as a plasma biomarker associated with breast cancer bone metastasis. Cancer Epidemiol Biomarkers Prev. 2013;22:972\u201383. https:\/\/doi.org\/10.1158\/1055-9965.EPI-12-1318-T.","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"1394_CR16","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1016\/j.ejca.2010.02.026","volume":"46","author":"T Ara","year":"2010","unstructured":"Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223\u201331. https:\/\/doi.org\/10.1016\/j.ejca.2010.02.026.","journal-title":"Eur J Cancer"},{"key":"1394_CR17","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1006\/jsre.2001.6204","volume":"100","author":"AT Mancino","year":"2001","unstructured":"Mancino AT, Klimberg VS, Yamamoto M, Manolagas SC, Abe E. Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res. 2001;100:18\u201324. https:\/\/doi.org\/10.1006\/jsre.2001.6204.","journal-title":"J Surg Res"},{"key":"1394_CR18","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nm1519","volume":"13","author":"BK Park","year":"2007","unstructured":"Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, Gu K, Shah V, Pei L, Zarbo RJ, et al. NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med. 2007;13:62\u20139. https:\/\/doi.org\/10.1038\/nm1519.","journal-title":"Nat Med"},{"key":"1394_CR19","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/nm849","volume":"9","author":"LW Chen","year":"2003","unstructured":"Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med. 2003;9:575\u201381. https:\/\/doi.org\/10.1038\/nm849.","journal-title":"Nat Med"},{"key":"1394_CR20","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.ccr.2008.06.016","volume":"14","author":"T Sakurai","year":"2008","unstructured":"Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell. 2008;14:156\u201365. https:\/\/doi.org\/10.1016\/j.ccr.2008.06.016.","journal-title":"Cancer Cell"},{"key":"1394_CR21","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41576-019-0158-7","volume":"20","author":"LS Kristensen","year":"2019","unstructured":"Kristensen LS, Andersen MS, Stagsted L, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675\u201391. https:\/\/doi.org\/10.1038\/s41576-019-0158-7.","journal-title":"Nat Rev Genet"},{"key":"1394_CR22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s12943-020-01183-9","volume":"19","author":"X Zheng","year":"2020","unstructured":"Zheng X, Huang M, Xing L, Yang R, Wang X, Jiang R, Zhang L, Chen J. The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. Mol Cancer. 2020;19:73. https:\/\/doi.org\/10.1186\/s12943-020-01183-9.","journal-title":"Mol Cancer"},{"key":"1394_CR23","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12943-020-01152-2","volume":"19","author":"G Liang","year":"2020","unstructured":"Liang G, Ling Y, Mehrpour M, Saw PE, Liu Z, Tan W, Tian Z, Zhong W, Lin W, Luo Q, et al. Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression. Mol Cancer. 2020;19:65. https:\/\/doi.org\/10.1186\/s12943-020-01152-2.","journal-title":"Mol Cancer"},{"key":"1394_CR24","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1016\/j.ymthe.2019.05.011","volume":"27","author":"Y Sang","year":"2019","unstructured":"Sang Y, Chen B, Song X, Li Y, Liang Y, Han D, Zhang N, Zhang H, Liu Y, Chen T, et al. circRNA_0025202 regulates tamoxifen sensitivity and tumor progression via regulating the miR-182-5p\/FOXO3a axis in breast cancer. Mol Ther. 2019;27:1638\u201352. https:\/\/doi.org\/10.1016\/j.ymthe.2019.05.011.","journal-title":"Mol Ther"},{"key":"1394_CR25","doi-asserted-by":"publisher","first-page":"41028","DOI":"10.1074\/jbc.M006179200","volume":"275","author":"F Carlotti","year":"2000","unstructured":"Carlotti F, Dower SK, Qwarnstrom EE. Dynamic shuttling of nuclear factor kappa B between the nucleus and cytoplasm as a consequence of inhibitor dissociation. J Biol Chem. 2000;275:41028\u201334. https:\/\/doi.org\/10.1074\/jbc.M006179200.","journal-title":"J Biol Chem"},{"key":"1394_CR26","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1073\/pnas.91.1.28","volume":"91","author":"PJ Chiao","year":"1994","unstructured":"Chiao PJ, Miyamoto S, Verma IM. Autoregulation of I kappa B alpha activity. Proc Natl Acad Sci U S A. 1994;91:28\u201332. https:\/\/doi.org\/10.1073\/pnas.91.1.28.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1394_CR27","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.1128\/mcb.15.5.2689","volume":"15","author":"F Arenzana-Seisdedos","year":"1995","unstructured":"Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol. 1995;15:2689\u201396. https:\/\/doi.org\/10.1128\/mcb.15.5.2689.","journal-title":"Mol Cell Biol"},{"key":"1394_CR28","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nrd3244","volume":"9","author":"R Rizzoli","year":"2010","unstructured":"Rizzoli R, Yasothan U, Kirkpatrick P. Denosumab. Nat Rev Drug Discov. 2010;9:591\u20132. https:\/\/doi.org\/10.1038\/nrd3244.","journal-title":"Nat Rev Drug Discov"},{"key":"1394_CR29","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1093\/jnci\/djh141","volume":"96","author":"F Saad","year":"2004","unstructured":"Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879\u201382. https:\/\/doi.org\/10.1093\/jnci\/djh141.","journal-title":"J Natl Cancer Inst"},{"key":"1394_CR30","doi-asserted-by":"publisher","first-page":"272","DOI":"10.4103\/2278-330X.119895","volume":"2","author":"P Narayanan","year":"2013","unstructured":"Narayanan P. Denosumab: a comprehensive review. South Asian J Cancer. 2013;2:272\u20137. https:\/\/doi.org\/10.4103\/2278-330X.119895.","journal-title":"South Asian J Cancer"},{"key":"1394_CR31","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.ccell.2016.09.011","volume":"30","author":"Y Liu","year":"2016","unstructured":"Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016;30:668\u201381. https:\/\/doi.org\/10.1016\/j.ccell.2016.09.011.","journal-title":"Cancer Cell"},{"key":"1394_CR32","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1007\/s10555-013-9420-1","volume":"32","author":"J Sceneay","year":"2013","unstructured":"Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32:449\u201364. https:\/\/doi.org\/10.1007\/s10555-013-9420-1.","journal-title":"Cancer Metastasis Rev"},{"issue":"7","key":"1394_CR33","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3390\/cancers10070218","volume":"10","author":"A Maurizi","year":"2018","unstructured":"Maurizi A, Rucci N. The osteoclast in bone metastasis: player and target. Cancers (Basel). 2018;10(7):218. https:\/\/doi.org\/10.3390\/cancers10070218.","journal-title":"Cancers (Basel)"},{"key":"1394_CR34","doi-asserted-by":"publisher","first-page":"4606","DOI":"10.1158\/0008-5472.CAN-13-0305","volume":"73","author":"A Sawant","year":"2013","unstructured":"Sawant A, Ponnazhagan S. Myeloid-derived suppressor cells as osteoclast progenitors: a novel target for controlling osteolytic bone metastasis. Cancer Res. 2013;73:4606\u201310. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-0305.","journal-title":"Cancer Res"},{"key":"1394_CR35","doi-asserted-by":"publisher","first-page":"8726","DOI":"10.1038\/s41598-019-45278-w","volume":"9","author":"J Kang","year":"2019","unstructured":"Kang J, Choi YJ, Seo BY, Jo U, Park SI, Kim YH, Park KH. A selective FGFR inhibitor AZD4547 suppresses RANKL\/M-CSF\/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment. Sci Rep. 2019;9:8726. https:\/\/doi.org\/10.1038\/s41598-019-45278-w.","journal-title":"Sci Rep"},{"key":"1394_CR36","doi-asserted-by":"publisher","first-page":"2520","DOI":"10.1111\/j.1538-7836.2007.02784.x","volume":"5","author":"PJ Hohensinner","year":"2007","unstructured":"Hohensinner PJ, Kaun C, Rychli K, Niessner A, Pfaffenberger S, Rega G, de Martin R, Maurer G, Ullrich R, Huber K, Wojta J. Macrophage colony stimulating factor expression in human cardiac cells is upregulated by tumor necrosis factor-alpha via an NF-kappaB dependent mechanism. J Thromb Haemost. 2007;5:2520\u20138. https:\/\/doi.org\/10.1111\/j.1538-7836.2007.02784.x.","journal-title":"J Thromb Haemost"},{"key":"1394_CR37","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1128\/mcb.10.3.1281-1286.1990","volume":"10","author":"R Schreck","year":"1990","unstructured":"Schreck R, Baeuerle PA. NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene. Mol Cell Biol. 1990;10:1281\u20136. https:\/\/doi.org\/10.1128\/mcb.10.3.1281-1286.1990.","journal-title":"Mol Cell Biol"},{"key":"1394_CR38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028081","volume":"6","author":"Y Wang","year":"2011","unstructured":"Wang Y, Mo X, Piper MG, Wang H, Parinandi NL, Guttridge D, Marsh CB. M-CSF induces monocyte survival by activating NF-kappaB p65 phosphorylation at Ser276 via protein kinase C. PLoS One. 2011;6: e28081. https:\/\/doi.org\/10.1371\/journal.pone.0028081.","journal-title":"PLoS One"},{"key":"1394_CR39","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1007\/s12035-013-8550-3","volume":"49","author":"JK Choi","year":"2014","unstructured":"Choi JK, Kim KH, Park SR, Choi BH. Granulocyte macrophage colony-stimulating factor shows anti-apoptotic activity via the PI3K-NF-kappaB-HIF-1alpha-survivin pathway in mouse neural progenitor cells. Mol Neurobiol. 2014;49:724\u201333. https:\/\/doi.org\/10.1007\/s12035-013-8550-3.","journal-title":"Mol Neurobiol"},{"key":"1394_CR40","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bbrc.2004.06.097","volume":"321","author":"JM Hodge","year":"2004","unstructured":"Hodge JM, Kirkland MA, Nicholson GC. GM-CSF cannot substitute for M-CSF in human osteoclastogenesis. Biochem Biophys Res Commun. 2004;321:7\u201312. https:\/\/doi.org\/10.1016\/j.bbrc.2004.06.097.","journal-title":"Biochem Biophys Res Commun"},{"key":"1394_CR41","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/s8756-3282(00)00453-1","volume":"28","author":"Y Fujikawa","year":"2001","unstructured":"Fujikawa Y, Sabokbar A, Neale SD, Itonaga I, Torisu T, Athanasou NA. The effect of macrophage-colony stimulating factor and other humoral factors (interleukin-1, -3, -6, and -11, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor) on human osteoclast formation from circulating cells. Bone. 2001;28:261\u20137. https:\/\/doi.org\/10.1016\/s8756-3282(00)00453-1.","journal-title":"Bone"}],"container-title":["Molecular Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-021-01394-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12943-021-01394-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-021-01394-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T02:04:36Z","timestamp":1627524276000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecular-cancer.biomedcentral.com\/articles\/10.1186\/s12943-021-01394-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1394"],"URL":"https:\/\/doi.org\/10.1186\/s12943-021-01394-8","relation":{},"ISSN":["1476-4598"],"issn-type":[{"value":"1476-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]},"assertion":[{"value":"8 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All Patients\u2019 samples were obtained according to the Declaration of Helsinki and each patient signed a written informed consent for all the procedures. All of the animal procedures were approved by the Sun Yat-sen University Animal Care Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors state that there are no competing interests in this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"98"}}