{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:37:43Z","timestamp":1790905063019,"version":"4.1.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T00:00:00Z","timestamp":1572998400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T00:00:00Z","timestamp":1572998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772277"],"award-info":[{"award-number":["81772277"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The regulatory non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), emerge as pivotal markers during tumor progression. Abnormal sialylated glycoprotein often leads to the malignancy of colorectal cancer (CRC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Differential levels of HOTAIR and\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      are analyzed by qRT-PCR. Functionally, CRC cell proliferation, aggressiveness and apoptosis are measured through relevant experiments, including CCK8 assay, colony formation assay, transwell assay, western blot and flow cytometry. Dual-luciferase reporter gene assay and RIP assay confirm the direct interaction between HOTAIR and miR-214. The lung metastasis, liver metatstasis and xenografts nude mice models are established to show the in vivo effect of HOATIR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, differential levels of HOTAIR and\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      are primarily observed in CRC samples and cells. Upregulated HOTAIR and\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      are crucial predictors for poor CRC prognosis. Altered level of\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      modulates CRC malignancy. Furthermore,\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      and HOTAIR are confirmed as the direct targets of miR-214, and\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      is regulated by HOTAIR via sponging miR-214. ST6GAL1 induces the elevated metabolic sialylation of c-Met, which is co-mediated by HOTAIR and miR-214. Sialylated c-Met affects the activity of JAK2\/STAT3 pathway. The regulatory role of HOTAIR\/miR-214\/\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      axis also impacts CRC procession. In addition, HOTAIR mediates lung metastasis, liver metastasis and tumorigenesis in vivo. ShHOTAIR and AMG-208 are combined to inhibit tumorigenesis for successful drug development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The HOTAIR\/miR-214\/\n                      <jats:italic>ST6GAL1<\/jats:italic>\n                      axis commands the CRC malignancy by modifying c-Met with sialylation and activating JAK2\/STAT3 pathway. Our study presents novel insights into CRC progression and provided prospective therapeutic target for CRC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-019-1468-5","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T09:03:27Z","timestamp":1573031007000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["The HOTAIR\/miR-214\/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2\/STAT3 cascade"],"prefix":"10.1186","volume":"38","author":[{"given":"Bing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimeng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangda","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-3253","authenticated-orcid":false,"given":"Li","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,6]]},"reference":[{"key":"1468_CR1","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1158\/1078-0432.CCR-17-1960","volume":"24","author":"BS Roberts","year":"2018","unstructured":"Roberts BS, Hardigan AA, Moore DE, Ramaker RC, Jones AL, Fitz-Gerald MB, et al. Discovery and validation of circulating biomarkers of colorectal adenoma by high-depth small RNA sequencing. Clin Cancer Res. 2018;24:2092\u20139.","journal-title":"Clin Cancer Res"},{"key":"1468_CR2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3322\/caac.21395","volume":"67","author":"RL Siegel","year":"2017","unstructured":"Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67:177\u201393.","journal-title":"CA Cancer J Clin"},{"key":"1468_CR3","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1158\/0008-5472.CAN-07-1340","volume":"68","author":"M Hedlund","year":"2008","unstructured":"Hedlund M, Ng E, Varki A, Varki NM. alpha 2\u20136-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo. Cancer Res. 2008;68:388\u201394.","journal-title":"Cancer Res"},{"key":"1468_CR4","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1136\/gut.46.3.359","volume":"46","author":"T Petretti","year":"2000","unstructured":"Petretti T, Kemmner W, Schulze B, Schlag PM. Altered mRNA expression of glycosyltransferases in human colorectal carcinomas and liver metastases. Gut. 2000;46:359\u201366.","journal-title":"Gut."},{"key":"1468_CR5","doi-asserted-by":"crossref","first-page":"65374","DOI":"10.18632\/oncotarget.11699","volume":"7","author":"A Wei","year":"2016","unstructured":"Wei A, Fan B, Zhao Y, Zhang H, Wang L, Yu X, et al. ST6Gal-I overexpression facilitates prostate cancer progression via the PI3K\/Akt\/GSK-3beta\/beta-catenin signaling pathway. Oncotarget. 2016;7:65374\u201388.","journal-title":"Oncotarget."},{"issue":"5","key":"1468_CR6","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1093\/glycob\/cwq200","volume":"21","author":"J Souady","year":"2011","unstructured":"Souady J, H\u00fclsewig M, Distler U, Haier J, Denz A, Pilarsky C, et al. Differences in CD75s- and iso-CD75s-ganglioside content and altered mRNA expression of sialyltransferases ST6GAL1 and ST3GAL6 in human hepatocellular carcinomas and nontumoral liver tissues. Glycobiology. 2011;21(5):584\u201394.","journal-title":"Glycobiology."},{"key":"1468_CR7","doi-asserted-by":"publisher","first-page":"629","DOI":"10.5009\/gnl.2013.7.6.629","volume":"7","author":"JJ Park","year":"2013","unstructured":"Park JJ, Lee M. Increasing the alpha 2, 6 sialylation of glycoproteins may contribute to metastatic spread and therapeutic resistance in colorectal cancer. Gut Liver. 2013;7:629\u201341.","journal-title":"Gut Liver"},{"key":"1468_CR8","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/aps.2009.84","volume":"30","author":"J Qian","year":"2009","unstructured":"Qian J, Zhu CH, Tang S, Shen AJ, Ai J, Li J, et al. alpha2, 6-hyposialylation of c-met abolishes cell motility of ST6Gal-I-knockdown HCT116 cells. Acta Pharmacol Sin. 2009;30:1039\u201345.","journal-title":"Acta Pharmacol Sin"},{"key":"1468_CR9","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1158\/1535-7163.MCT-16-0472","volume":"16","author":"R Salgia","year":"2017","unstructured":"Salgia R. MET in lung Cancer: biomarker selection based on scientific rationale. Mol Cancer Ther. 2017;16:555\u201365.","journal-title":"Mol Cancer Ther"},{"key":"1468_CR10","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.canlet.2018.02.013","volume":"420","author":"W Hassan","year":"2018","unstructured":"Hassan W, Chitcholtan K, Sykes P, Garrill A. Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells. Cancer Lett. 2018;420:168\u201381.","journal-title":"Cancer Lett"},{"key":"1468_CR11","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1016\/j.celrep.2014.05.032","volume":"7","author":"S Van Schaeybroeck","year":"2014","unstructured":"Van Schaeybroeck S, Kalimutho M, Dunne PD, Carson R, Allen W, Jithesh PV, et al. ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep. 2014;7:1940\u201355.","journal-title":"Cell Rep"},{"key":"1468_CR12","doi-asserted-by":"publisher","first-page":"13875","DOI":"10.1038\/ncomms13875","volume":"7","author":"ND Damas","year":"2016","unstructured":"Damas ND, Marcatti M, Come C, Christensen LL, Nielsen MM, Baumgartner R, et al. SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nat Commun. 2016;7:13875.","journal-title":"Nat Commun"},{"key":"1468_CR13","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1158\/1535-7163.MCT-14-0695","volume":"14","author":"ZZ Zhang","year":"2015","unstructured":"Zhang ZZ, Shen ZY, Shen YY, Zhao EH, Wang M, Wang CJ, et al. HOTAIR Long noncoding RNA promotes gastric Cancer metastasis through suppression of poly r(C)-binding protein (PCBP) 1. Mol Cancer Ther. 2015;14:1162\u201370.","journal-title":"Mol Cancer Ther"},{"key":"1468_CR14","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.cbi.2018.03.010","volume":"286","author":"Y Zhang","year":"2018","unstructured":"Zhang Y, Cheng X, Liang H, Jin Z. Long non-coding RNA HOTAIR and STAT3 synergistically regulate the cervical cancer cell migration and invasion. Chem Biol Interact. 2018;286:106\u201310.","journal-title":"Chem Biol Interact"},{"key":"1468_CR15","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.omtn.2017.07.007","volume":"8","author":"P Li","year":"2017","unstructured":"Li P, Zhang X, Wang L, Du L, Yang Y, Liu T, et al. lncRNA HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kappaB\/TS signaling in colorectal Cancer. Mol Therapy Nucleic Acids. 2017;8:356\u201369.","journal-title":"Mol Therapy Nucleic Acids"},{"key":"1468_CR16","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","volume":"136","author":"DP Bartel","year":"2009","unstructured":"Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215\u201333.","journal-title":"Cell."},{"key":"1468_CR17","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41389-018-0028-8","volume":"7","author":"JL Hu","year":"2018","unstructured":"Hu JL, He GY, Lan XL, Zeng ZC, Guan J, Ding Y, et al. Inhibition of ATG12-mediated autophagy by miR-214 enhances radiosensitivity in colorectal cancer. Oncogenesis. 2018;7:16.","journal-title":"Oncogenesis."},{"key":"1468_CR18","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s12935-017-0471-1","volume":"17","author":"Y Li","year":"2017","unstructured":"Li Y, Li Y, Chen Y, Xie Q, Dong N, Gao Y, et al. MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis. Cancer Cell Int. 2017;17:102.","journal-title":"Cancer Cell Int"},{"key":"1468_CR19","doi-asserted-by":"publisher","first-page":"325","DOI":"10.12659\/MSM.894913","volume":"22","author":"L Dong","year":"2016","unstructured":"Dong L, Hui L. HOTAIR promotes proliferation, migration, and invasion of ovarian Cancer SKOV3 cells through regulating PIK3R3. Medical Sci Monitor: Int Med J Exp Clin Res. 2016;22:325\u201331.","journal-title":"Medical Sci Monitor: Int Med J Exp Clin Res"},{"key":"1468_CR20","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1021\/pr400861m","volume":"13","author":"MK Sethi","year":"2014","unstructured":"Sethi MK, Thaysen-Andersen M, Smith JT, Baker MS, Packer NH. Hancock WS et al comparative N-glycan profiling of colorectal cancer cell lines reveals unique bisecting GlcNAc and alpha-2, 3-linked sialic acid determinants are associated with membrane proteins of the more metastatic\/aggressive cell lines. J Proteome Res. 2014;13:277\u201388.","journal-title":"J Proteome Res"},{"key":"1468_CR21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1748-717X-7-47","volume":"7","author":"M Lee","year":"2012","unstructured":"Lee M, Park JJ, Ko YG, Lee YS. Cleavage of ST6Gal I by radiation-induced BACE1 inhibits golgi-anchored ST6Gal I-mediated sialylation of integrin \u03b21 and migration in colon cancer cells. Radiat Oncol. 2012;7:47.","journal-title":"Radiat Oncol"},{"key":"1468_CR22","doi-asserted-by":"publisher","first-page":"34627","DOI":"10.1074\/jbc.M114.593392","volume":"289","author":"J Lu","year":"2014","unstructured":"Lu J, Isaji T, Im S, Fukuda T, Hashii N, Takakura D, et al. beta-Galactoside alpha2,6-sialyltranferase 1 promotes transforming growth factor-beta-mediated epithelial-mesenchymal transition. J Biol Chem. 2014;289:34627\u201341.","journal-title":"J Biol Chem"},{"key":"1468_CR23","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1186\/1471-2407-13-464","volume":"13","author":"XH Liu","year":"2013","unstructured":"Liu XH, Liu ZL, Sun M, Liu J, Wang ZX, De W. The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer. 2013;13:464.","journal-title":"BMC Cancer"},{"key":"1468_CR24","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/hep.27118","volume":"60","author":"DL Chen","year":"2014","unstructured":"Chen DL, Wang ZQ, Zeng ZL, Wu WJ, Zhang DS, Luo HY, et al. Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression. Hepatology. 2014;60:598\u2013609.","journal-title":"Hepatology."},{"key":"1468_CR25","doi-asserted-by":"publisher","first-page":"645","DOI":"10.3892\/ol.2014.2746","volume":"9","author":"LM Long","year":"2015","unstructured":"Long LM, He BF, Huang GQ, Guo YH, Liu YS, Huo JR. microRNA-214 functions as a tumor suppressor in human colon cancer via the suppression of ADP-ribosylation factor-like protein 2. Oncol Lett. 2015;9:645\u201350.","journal-title":"Oncol Lett"},{"key":"1468_CR26","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.4049\/jimmunol.1001633","volume":"186","author":"LM Li","year":"2011","unstructured":"Li LM, Hou DX, Guo YL, Yang JW, Liu Y, Zhang CY, et al. Role of microRNA-214-targeting phosphatase and tensin homolog in advanced glycation end product-induced apoptosis delay in monocytes. J Immunol. 2011;186:2552\u201360.","journal-title":"J Immunol"},{"key":"1468_CR27","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1073\/pnas.94.2.701","volume":"94","author":"H Takayama","year":"1997","unstructured":"Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, et al. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor\/scatter factor. Proc Natl Acad Sci U S A. 1997;94:701\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1468_CR28","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1002\/jcb.20459","volume":"95","author":"A Cramer","year":"2005","unstructured":"Cramer A, Kleiner S, Westermann M, Meissner A, Lange A, Friedrich K. Activation of the c-met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3. J Cell Biochem. 2005;95:805\u201316.","journal-title":"J Cell Biochem"},{"key":"1468_CR29","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1002\/cbf.3304","volume":"35","author":"KS Chandrasekaran","year":"2017","unstructured":"Chandrasekaran KS, Sathyanarayanan A, Karunagaran D. miR-214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells. Cell Biochem Funct. 2017;35:464\u201371.","journal-title":"Cell Biochem Funct"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-019-1468-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13046-019-1468-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-019-1468-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T19:47:07Z","timestamp":1604519227000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-019-1468-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,6]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1468"],"URL":"https:\/\/doi.org\/10.1186\/s13046-019-1468-5","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,6]]},"assertion":[{"value":"5 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study has been examined and certified by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (Ethics Reference NO: YJKY-FB-2016-16), and informed consent was obtained from all participants included in the study, in agreement with institutional guidelines.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"455"}}