{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:03:11Z","timestamp":1787497391457,"version":"build-2736575974"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2018A0303100021"],"award-info":[{"award-number":["2018A0303100021"]}],"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":["2019A1515010412"],"award-info":[{"award-number":["2019A1515010412"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971385"],"award-info":[{"award-number":["81971385"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81902751"],"award-info":[{"award-number":["81902751"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Researcher Cultivation Project of Shenzhen People's Hospital","award":["SYKYPY201927"],"award-info":[{"award-number":["SYKYPY201927"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biol Rep"],"published-print":{"date-parts":[[2021,6]]},"DOI":"10.1007\/s11033-021-06507-6","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T15:03:31Z","timestamp":1624633411000},"page":"5109-5119","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Abnormal H3K27 histone methylation of RASA1 gene leads to unexplained recurrent spontaneous abortion by regulating Ras-MAPK pathway in trophoblast cells"],"prefix":"10.1007","volume":"48","author":[{"given":"Jun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinqiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8159-6496","authenticated-orcid":false,"given":"Yali","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"6507_CR1","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/jog.13837","volume":"45","author":"LJ Ewington","year":"2019","unstructured":"Ewington LJ, Tewary S, Brosens JJ (2019) New insights into the mechanisms underlying recurrent pregnancy loss. J Obstet Gynaecol Res 45:258\u2013265","journal-title":"J Obstet Gynaecol Res"},{"key":"6507_CR2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00404-015-3922-8","volume":"294","author":"L Meng","year":"2016","unstructured":"Meng L, Lin J, Chen L, Wang Z, Liu M, Liu Y, Chen X, Zhu L, Chen H, Zhang J (2016) Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch Gynecol Obstet 294:29\u201339","journal-title":"Arch Gynecol Obstet"},{"key":"6507_CR3","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s43032-019-00003-w","volume":"27","author":"HN Liu","year":"2020","unstructured":"Liu HN, Tang XM, Wang XQ, Gao J, Li N, Wang YY, Xia HF (2020) MiR-93 Inhibits Trophoblast cell proliferation and promotes cell apoptosis by targeting BCL2L2 in recurrent spontaneous abortion. Reprod Sci 27:152\u2013162","journal-title":"Reprod Sci"},{"key":"6507_CR4","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1093\/jb\/mvz076","volume":"167","author":"L Wu","year":"2020","unstructured":"Wu L, Cheng B, Liu Q, Jiang P, Yang J (2020) CRY2 suppresses trophoblast migration and invasion in recurrent spontaneous abortion. J Biochem 167:79\u201387","journal-title":"J Biochem"},{"key":"6507_CR5","first-page":"424","volume":"102","author":"X Luan","year":"2020","unstructured":"Luan X, Li S, Zhao J, Zhai J, Liu X, Chen ZJ, Li W, Du Y (2020) Down-regulation of CCR7 via AKT pathway and GATA2 inactivation suppressed trophoblast migration and invasion in recurrent spontaneous abortion. Biol Reprod 102:424\u2013433","journal-title":"Biol Reprod"},{"key":"6507_CR6","first-page":"2623","volume":"17","author":"Q Xiao","year":"2019","unstructured":"Xiao Q, Zeng FL, Tang GY, Lei CY, Zou XX, Liu XL, Peng BL, Qin S, Li HX (2019) Expression of galectin-3 and apoptosis in placental villi from patients with missed abortion during early pregnancy. Exp Ther Med 17:2623\u20132631","journal-title":"Exp Ther Med"},{"key":"6507_CR7","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s00418-018-1699-0","volume":"150","author":"G Moser","year":"2018","unstructured":"Moser G, Windsperger K, Pollheimer J, de Sousa Lopes SC, Huppertz B (2018) Human trophoblast invasion: new and unexpected routes and functions. Histochem Cell Biol 150:361\u2013370","journal-title":"Histochem Cell Biol"},{"key":"6507_CR8","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.3389\/fphys.2018.01699","volume":"9","author":"CE Ab\u00e1n","year":"2018","unstructured":"Ab\u00e1n CE, Accialini PL, Etcheverry T, Leguizam\u00f3n GF, Martinez NA (2018) Farina MG crosstalk between nitric oxide and endocannabinoid signaling pathways in normal and pathological placentation. Front Physiol 9:1699","journal-title":"Front Physiol"},{"key":"6507_CR9","doi-asserted-by":"publisher","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","volume":"76","author":"M Kn\u00f6fler","year":"2019","unstructured":"Kn\u00f6fler M, Haider S, Saleh L, Pollheimer J, Gamage TKJB, James J (2019) Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell Mol Life Sci 76:3479\u20133496","journal-title":"Cell Mol Life Sci"},{"key":"6507_CR10","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1002\/jcp.27189","volume":"234","author":"A Afkham","year":"2019","unstructured":"Afkham A, Eghbal-Fard S, Heydarlou H, Azizi R, Aghebati-Maleki L, Yousefi M (2019) Toll-like receptors signaling network in pre-eclampsia: An updated review. J Cell Physiol 234:2229\u20132240","journal-title":"J Cell Physiol"},{"key":"6507_CR11","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.3892\/mmr.2017.6718","volume":"16","author":"Z Zhang","year":"2017","unstructured":"Zhang Z, Wang X, Zhang L, Shi Y, Wang J, Yan H (2017) Wnt\/\u03b2-catenin signaling pathway in trophoblast cells and abnormal activation in preeclampsia (Review). Mol Med Rep 16:1007\u20131013","journal-title":"Mol Med Rep"},{"key":"6507_CR12","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1111\/aji.12436","volume":"75","author":"SK Gupta","year":"2016","unstructured":"Gupta SK, Malhotra SS, Malik A, Verma S, Chaudhary P (2016) Cell signaling pathways involved during invasion and syncytialization of trophoblast cells. Am J Reprod Immunol 75:361\u2013371","journal-title":"Am J Reprod Immunol"},{"key":"6507_CR13","first-page":"1","volume":"18","author":"L Mo","year":"2020","unstructured":"Mo L, Hong S, Li Y, Hu Z, Han B, Wei Z, Jia J (2020) Sevoflurane inhibited inflammatory response induced by TNF-\u03b1 in human trophoblastic cells through p38MAPK signaling pathway. J Recept Signal Transduct Res 18:1\u20136","journal-title":"J Recept Signal Transduct Res"},{"key":"6507_CR14","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.bbabio.2018.05.003","volume":"1859","author":"L Dard","year":"2018","unstructured":"Dard L, Bellance N, Lacombe D, Rossignol R (2018) RAS signalling in energy metabolism and rare human diseases. Biochim Biophys Acta Bioenerg 1859:845\u2013867","journal-title":"Biochim Biophys Acta Bioenerg"},{"key":"6507_CR15","doi-asserted-by":"publisher","first-page":"5185","DOI":"10.1172\/JCI124649","volume":"128","author":"L Al-Olabi","year":"2018","unstructured":"Al-Olabi L, Polubothu S, Dowsett K, Andrews KA, Stadnik P, Joseph AP, Knox R, Pittman A, Clark G, Baird W et al (2018) Mosaic RAS\/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest 128:5185","journal-title":"J Clin Invest"},{"key":"6507_CR16","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.molmed.2019.01.009","volume":"25","author":"X Zeng","year":"2019","unstructured":"Zeng X, Hunt A, Jin SC, Duran D, Gaillard J, Kahle KT (2019) EphrinB2-EphB4-RASA1 signaling in human cerebrovascular development and disease. Trends Mol Med 25:265\u2013286","journal-title":"Trends Mol Med"},{"key":"6507_CR17","doi-asserted-by":"publisher","first-page":"23885","DOI":"10.18632\/oncotarget.8127","volume":"7","author":"H Sung","year":"2016","unstructured":"Sung H, Kanchi KL, Wang X, Hill KS, Messina JL, Lee JH, Kim Y, Dees ND, Ding L, Teer JK et al (2016) Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. Oncotarget 7:23885\u201323896","journal-title":"Oncotarget"},{"key":"6507_CR18","first-page":"1","volume":"21","author":"L Li","year":"2019","unstructured":"Li L, Fan Y, Huang X, Luo J, Zhong L, Shu XS, Lu L, Xiang T, Chan ATC, Yeo W et al (2019) Tumor suppression of ras GTPase-activating protein RASA5 through antagonizing ras signaling perturbation in carcinomas. Science 21:1\u201318","journal-title":"Science"},{"key":"6507_CR19","doi-asserted-by":"publisher","first-page":"100","DOI":"10.3389\/fendo.2018.00100","volume":"9","author":"M Liu","year":"2018","unstructured":"Liu M, Wang Y, Lu H, Wang H, Shi X, Shao X, Li YX, Zhao Y, Wang YL (2018) miR-518b enhances human trophoblast cell proliferation through targeting Rap1b and activating Ras-MAPK signal. Front Endocrinol (Lausanne) 9:100","journal-title":"Front Endocrinol (Lausanne)"},{"key":"6507_CR20","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1093\/molehr\/gaz010","volume":"25","author":"AL Arthurs","year":"2019","unstructured":"Arthurs AL, Lumbers ER, Pringle KG (2019) MicroRNA mimics that target the placental renin-angiotensin system inhibit trophoblast proliferation. Mol Hum Reprod 25:218\u2013227","journal-title":"Mol Hum Reprod"},{"key":"6507_CR21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.biopha.2017.01.026","volume":"88","author":"C Liu","year":"2017","unstructured":"Liu C, Liang X, Wang J, Zheng Q, Zhao Y, Khan MN, Liu S, Yan Q (2017) Protein O-fucosyltransferase 1 promotes trophoblast cell proliferation through activation of MAPK and PI3K\/Akt signaling pathways. Biomed Pharmacother 88:95\u2013101","journal-title":"Biomed Pharmacother"},{"key":"6507_CR22","doi-asserted-by":"publisher","first-page":"796","DOI":"10.3109\/09513590.2015.1069268","volume":"31","author":"HY Zhu","year":"2015","unstructured":"Zhu HY, Wang JX, Tong XM, Xue YM, Zhang SY (2015) S100P regulates trophoblast-like cell proliferation via P38 MAPK pathway. Gynecol Endocrinol 31:796\u2013800","journal-title":"Gynecol Endocrinol"},{"key":"6507_CR23","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.placenta.2015.03.004","volume":"36","author":"Z Wang","year":"2015","unstructured":"Wang Z, Liu M, Nie X, Zhang Y, Chen Y, Zhu L, Chen X, Chen L, Chen H, Zhang J (2015) NOD1 and NOD2 control the invasiveness of trophoblast cells via the MAPK\/p38 signaling pathway in human first-trimester pregnancy. Placenta 36:652\u2013660","journal-title":"Placenta"},{"key":"6507_CR24","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.trecan.2019.12.005","volume":"6","author":"JB Post","year":"2020","unstructured":"Post JB, Roodhart JML, Snippert HJG (2020) Colorectal cancer modeling with organoids: discriminating between oncogenic RAS and BRAF variants. Trends Cancer 6:111\u2013129","journal-title":"Trends Cancer"},{"key":"6507_CR25","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.238865","author":"DR Harrell Stewart","year":"2020","unstructured":"Harrell Stewart DR, Clark GJ (2020) Pumping the brakes on RAS - negative regulators and death effectors of RAS. J Cell Sci. https:\/\/doi.org\/10.1242\/jcs.238865","journal-title":"J Cell Sci"},{"key":"6507_CR26","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.3389\/fonc.2019.01556","volume":"9","author":"S Deng","year":"2020","unstructured":"Deng S, Clowers MJ, Velasco WV, Ramos-Castaneda M, Moghaddam SJ (2020) Understanding the complexity of the tumor microenvironment in K-ras mutant lung cancer: finding an alternative path to prevention and treatment. Front Oncol 9:1556","journal-title":"Front Oncol"},{"key":"6507_CR27","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1006\/excr.1993.1139","volume":"206","author":"CH Graham","year":"1993","unstructured":"Graham CH, Hawley TS, Hawley RG, MacDougall JR, Kerbel RS, Khoo N, Lala PK (1993) Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res 206:204\u2013211","journal-title":"Exp Cell Res"},{"key":"6507_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.placenta.2016.12.007","volume":"50","author":"W Abou-Kheir","year":"2017","unstructured":"Abou-Kheir W, Barrak J, Hadadeh O, Daoud G (2017) HTR-8\/SVneo cell line contains a mixed population of cells. Placenta 50:1\u20137","journal-title":"Placenta"},{"key":"6507_CR29","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1172\/JCI124917","volume":"130","author":"D Chen","year":"2019","unstructured":"Chen D, Teng JM, North PE, Lapinski PE, King PD (2019) RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development. J Clin Invest 130:3545\u20133561","journal-title":"J Clin Invest"},{"key":"6507_CR30","doi-asserted-by":"publisher","first-page":"198","DOI":"10.3390\/cells9010198","volume":"9","author":"U Degirmenci","year":"2020","unstructured":"Degirmenci U, Wang M, Hu J (2020) Targeting aberrant RAS\/RAF\/MEK\/ERK signaling for cancer therapy. Cells 9:198","journal-title":"Cells"}],"container-title":["Molecular Biology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11033-021-06507-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11033-021-06507-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11033-021-06507-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T09:10:18Z","timestamp":1627463418000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11033-021-06507-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6]]},"references-count":30,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["6507"],"URL":"https:\/\/doi.org\/10.1007\/s11033-021-06507-6","relation":{},"ISSN":["0301-4851","1573-4978"],"issn-type":[{"value":"0301-4851","type":"print"},{"value":"1573-4978","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6]]},"assertion":[{"value":"15 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 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":"No potential conflicts of interest were disclosed.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethic committee of the Shenzhen People\u2019s Hospital.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All patients in the present study provided written informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have read the manuscript and approved the final version.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}