{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T22:00:13Z","timestamp":1783720813744,"version":"3.55.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"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":["820726357, and 82072635"],"award-info":[{"award-number":["820726357, and 82072635"]}],"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":["82173149"],"award-info":[{"award-number":["82173149"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"High-level Hospital Construction Research Project of Heyuan People's Hospital","award":["YNKT202202"],"award-info":[{"award-number":["YNKT202202"]}]},{"name":"Science and Technology Program of Heyuan","award":["23051017147335"],"award-info":[{"award-number":["23051017147335"]}]},{"name":"Science and Technology Program of Guangzhou","award":["2024A04J10016"],"award-info":[{"award-number":["2024A04J10016"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Direct"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of <jats:italic>LINC00909<\/jats:italic> in regulating pancreatic cancer stemness and cancer metastasis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The expression level and clinical characteristics of <jats:italic>LINC00909<\/jats:italic> were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People\u2019s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding <jats:italic>LINC00909<\/jats:italic> was experimented for subsequent bioinformatics analysis. The effect of <jats:italic>LINC00909<\/jats:italic> in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between <jats:italic>LINC00909<\/jats:italic> with <jats:italic>SMAD4<\/jats:italic> and the pluripotency factors were studied.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>LINC00909<\/jats:italic> was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of <jats:italic>LINC00909<\/jats:italic> enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of <jats:italic>LINC00909<\/jats:italic> decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, <jats:italic>LINC00909<\/jats:italic> inversely regulated <jats:italic>SMAD4<\/jats:italic> expression, knock-down of SMAD4 rescued the effect of <jats:italic>LINC00909<\/jats:italic>-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of <jats:italic>LINC00909<\/jats:italic> on pluripotency factors and CSC phenotype was dependent on <jats:italic>SMAD4<\/jats:italic> and MAPK\/JNK signaling pathway, another downstream pathway of <jats:italic>SMAD4<\/jats:italic> was also activated by <jats:italic>LINC00909.<\/jats:italic> Specifically, <jats:italic>LINC00909<\/jats:italic> was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the <jats:italic>SMAD4<\/jats:italic> mRNA. Finally, we found over-expression of <jats:italic>LINC00909<\/jats:italic> not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>We demonstrate <jats:italic>LINC00909<\/jats:italic> inhibits <jats:italic>SMAD4<\/jats:italic> expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK\/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13062-024-00463-4","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T09:05:16Z","timestamp":1710839116000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4"],"prefix":"10.1186","volume":"19","author":[{"given":"Zhenchong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuyi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkai","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunsheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqian","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanzhou","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanzhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"463_CR1","doi-asserted-by":"crossref","unstructured":"Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. LANCET. 2016;388:73.","DOI":"10.1016\/S0140-6736(16)00141-0"},{"key":"463_CR2","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1016\/S0140-6736(20)30974-0","volume":"395","author":"JD Mizrahi","year":"2020","unstructured":"Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020;395:2008.","journal-title":"Lancet"},{"key":"463_CR3","doi-asserted-by":"crossref","unstructured":"Xiao Z et al. Molecular mechanism underlying lymphatic metastasis in pancreatic cancer. BIOMED RES INT. 2014;2014:925845.","DOI":"10.1155\/2014\/925845"},{"issue":"819","key":"463_CR4","first-page":"e12","volume":"148","author":"SS Vege","year":"2015","unstructured":"Vege SS, Ziring B, Jain R, Moayyedi P. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148(819):e12.","journal-title":"Gastroenterology"},{"key":"463_CR5","doi-asserted-by":"crossref","unstructured":"Zhou P et al. The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer. MOL CANCER. 2017;16:52.","DOI":"10.1186\/s12943-017-0624-9"},{"key":"463_CR6","doi-asserted-by":"crossref","unstructured":"Morel AP et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLOS ONE. 2008;3:e2888.","DOI":"10.1371\/journal.pone.0002888"},{"key":"463_CR7","doi-asserted-by":"crossref","unstructured":"Mani SA et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. CELL. 2008;133:704.","DOI":"10.1016\/j.cell.2008.03.027"},{"key":"463_CR8","doi-asserted-by":"crossref","unstructured":"Yang L et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.","DOI":"10.1038\/s41392-020-0110-5"},{"key":"463_CR9","doi-asserted-by":"crossref","unstructured":"Hahn SA et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. SCIENCE. 1996;271:350.","DOI":"10.1126\/science.271.5247.350"},{"key":"463_CR10","doi-asserted-by":"publisher","first-page":"3465","DOI":"10.3892\/ol.2016.4427","volume":"11","author":"X Zhang","year":"2016","unstructured":"Zhang X, Cao J, Pei Y, Zhang J, Wang Q. Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells. ONCOL LETT. 2016;11:3465.","journal-title":"ONCOL LETT"},{"key":"463_CR11","doi-asserted-by":"crossref","unstructured":"Moustakas A, Heldin CH. Mechanisms of TGFbeta-induced epithelial-mesenchymal transition. J CLIN MED. 2016;5.","DOI":"10.3390\/jcm5070063"},{"key":"463_CR12","doi-asserted-by":"crossref","unstructured":"Necsulea A et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. NATURE. 2014;505:635.","DOI":"10.1038\/nature12943"},{"key":"463_CR13","doi-asserted-by":"crossref","unstructured":"Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. NAT REV GENET 2009;10:155.","DOI":"10.1038\/nrg2521"},{"key":"463_CR14","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.canlet.2017.09.019","volume":"410","author":"Z Fu","year":"2017","unstructured":"Fu Z, et al. LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9. CANCER LETT. 2017;410:68.","journal-title":"CANCER LETT"},{"key":"463_CR15","doi-asserted-by":"publisher","first-page":"108965","DOI":"10.1016\/j.biopha.2019.108965","volume":"116","author":"Z Liu","year":"2019","unstructured":"Liu Z, et al. LINC00909 promotes tumor progression in human glioma through regulation of miR-194\/MUC1-C axis. BIOMED PHARMACOTHER. 2019;116:108965.","journal-title":"BIOMED PHARMACOTHER"},{"key":"463_CR16","doi-asserted-by":"crossref","unstructured":"Ma Z et al. ZMAT1 acts as a tumor suppressor in pancreatic ductal adenocarcinoma by inducing SIRT3\/p53 signaling pathway. J Exp Clin Cancer Res. 2022;41:130.","DOI":"10.1186\/s13046-022-02310-8"},{"key":"463_CR17","doi-asserted-by":"crossref","unstructured":"Yuan SX et al. Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1. HEPATOLOGY. 2016;63:499.","DOI":"10.1002\/hep.27893"},{"key":"463_CR18","doi-asserted-by":"crossref","unstructured":"Ormanns S et al. The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy. INT J MOL SCI. 2017;18.","DOI":"10.3390\/ijms18051094"},{"key":"463_CR19","doi-asserted-by":"crossref","unstructured":"Hoshino Y et al. Smad4 Decreases the Population of Pancreatic Cancer-Initiating Cells through Transcriptional Repression of ALDH1A1. AM J PATHOL. 2015;185:1457.","DOI":"10.1016\/j.ajpath.2015.01.011"},{"key":"463_CR20","doi-asserted-by":"crossref","unstructured":"Ozawa H et al. SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK\/JNK Activation in Head and Neck Cancer Cells. CLIN CANCER RES. 2017;23:5162.","DOI":"10.1158\/1078-0432.CCR-16-1686"},{"key":"463_CR21","doi-asserted-by":"crossref","unstructured":"Tan X et al. Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation. NAT COMMUN. 2021;12:4853.","DOI":"10.1038\/s41467-021-24898-9"},{"key":"463_CR22","doi-asserted-by":"crossref","unstructured":"Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22:96.","DOI":"10.1038\/s41580-020-00315-9"},{"key":"463_CR23","doi-asserted-by":"crossref","unstructured":"Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3\u2019 UTRs via Alu elements. NATURE. 2011;470:284.","DOI":"10.1038\/nature09701"},{"key":"463_CR24","doi-asserted-by":"crossref","unstructured":"Bridges MC, Daulagala AC, Kourtidis A. LNCcation: lncRNA localization and function. J CELL BIOL. 2021;220.","DOI":"10.1083\/jcb.202009045"},{"key":"463_CR25","doi-asserted-by":"crossref","unstructured":"Su W et al. Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer. MOL CANCER. 2017;16:142.","DOI":"10.1186\/s12943-017-0711-y"},{"key":"463_CR26","doi-asserted-by":"crossref","unstructured":"Zhou M, Guo X, Wang M, Qin R. The patterns of antisense long non-coding RNAs regulating corresponding sense genes in human cancers. J CANCER. 2021;12:1499.","DOI":"10.7150\/jca.49067"},{"key":"463_CR27","doi-asserted-by":"crossref","unstructured":"Zhou M et al. LncRNA FAM83H-AS1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing FAM83H mRNA to protect beta-catenin from degradation. J Exp Clin Cancer Res. 2022;41:288.","DOI":"10.1186\/s13046-022-02491-2"}],"container-title":["Biology Direct"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13062-024-00463-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13062-024-00463-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13062-024-00463-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T09:13:12Z","timestamp":1710839592000},"score":1,"resource":{"primary":{"URL":"https:\/\/biologydirect.biomedcentral.com\/articles\/10.1186\/s13062-024-00463-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["463"],"URL":"https:\/\/doi.org\/10.1186\/s13062-024-00463-4","relation":{},"ISSN":["1745-6150"],"issn-type":[{"value":"1745-6150","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]},"assertion":[{"value":"13 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2024","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 study was approved by the Ethics Association of Guangdong Provincial People\u2019s Hospital. All enrolled patients provided written informed consent before participation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The publication has been approved by all co-authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}