{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:25:26Z","timestamp":1791408326224,"version":"4.3.3"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T00:00:00Z","timestamp":1684886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre in Poland","doi-asserted-by":"publisher","award":["2020\/39\/O\/NZ4\/01732"],"award-info":[{"award-number":["2020\/39\/O\/NZ4\/01732"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)\/ceramide axis may predispose patients with PSC, PSC\/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC\/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P\/ceramide axis that can lead to MSI-H cancer progression in PSC\/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC.<\/jats:p>","DOI":"10.3390\/ijms24119175","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T01:59:13Z","timestamp":1684893553000},"page":"9175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Role of hsa-miR-125b-5p Interaction with S1P\/Ceramide Axis in the Potential Development of Inflammation-Associated Colon Cancer in Primary Sclerosing Cholangitis"],"prefix":"10.3390","volume":"24","author":[{"given":"Joanna","family":"Abramczyk","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2064-0545","authenticated-orcid":false,"given":"Malgorzata","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Hula","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland"},{"name":"Translational Medicine Group, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-8640","authenticated-orcid":false,"given":"Agnieszka","family":"Kempinska-Podhorodecka","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1053\/j.gastro.2010.09.004","article-title":"Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches","volume":"139","author":"Hirschfield","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1053\/j.gastro.2017.02.038","article-title":"Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate with Course of Primary Sclerosing Cholangitis","volume":"152","author":"Weismuller","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1136\/gut.48.4.526","article-title":"The Risk of Colorectal Cancer in Ulcerative Colitis: A Meta-Analysis","volume":"48","author":"Eaden","year":"2001","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1038\/nm.4191","article-title":"Classification and Characterization of Microsatellite Instability across 18 Cancer Types","volume":"22","author":"Hanse","year":"2016","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1093\/nar\/gki145","article-title":"DNA-Binding Properties of Arid Family Proteins","volume":"33","author":"Patsialou","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.biopha.2016.09.099","article-title":"The Role of Micrornas in Colorectal Cancer","volume":"84","author":"Mohammadi","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1158\/0008-5472.CAN-16-0359","article-title":"Oncomir or Tumor Suppressor? The Duplicity of Micrornas in Cancer","volume":"76","author":"Svoronos","year":"2016","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1161\/ATVBAHA.112.300068","article-title":"Micrornas in Immune Response and Macrophage Polarization","volume":"33","author":"Liu","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","first-page":"A100","article-title":"PWE-066 Microrna Signatures Can Differentiate between Inflamed and Non Inflamed Colonic Mucosa of Ulcerative Colitis Patients","volume":"67","author":"Valmiki","year":"2018","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1478-811X-12-30","article-title":"Good Guy or Bad Guy: The Opposing Roles of Microrna 125b in Cancer","volume":"12","author":"Edbauer","year":"2014","journal-title":"Cell Commun. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1756-8722-6-6","article-title":"Diverse Functions of miR-125 Family in Different Cell Contexts","volume":"6","author":"Sun","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1038\/leu.2012.90","article-title":"miR-125 in Normal and Malignant Hematopoiesis","volume":"26","author":"Shaham","year":"2012","journal-title":"Leukemia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.chembiol.2015.11.004","article-title":"Differential Regulation of Specific Sphingolipids in Colon Cancer Cells During Staurosporine-Induced Apoptosis","volume":"22","author":"Lizardo","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/365557a0","article-title":"Sphingosine-1-Phosphate as 2nd Messenger in Cell-Proliferation Induced by Pdgf and Fcs Mitogens","volume":"365","author":"Olivera","year":"1993","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.canlet.2003.08.034","article-title":"Ceramide Synthesis and Metabolism as a Target for Cancer Therapy","volume":"206","author":"Reynolds","year":"2004","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Machala, M., Prochazkova, J., Hofmanova, J., Kralikova, L., Slavik, J., Tylichova, Z., Ovesna, P., Kozubik, A., and Vondracek, J. (2019). Colon Cancer and Perturbations of the Sphingolipid Metabolism. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236051"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Blom, T., Bergelin, N., Meinander, A., Lof, C., Slotte, J.P., Eriksson, J.E., and Tornquist, K. (2010). An Autocrine Sphingosine-1-Phosphate Signaling Loop Enhances Nf-Kappab-Activation and Survival. BMC Cell Biol., 11.","DOI":"10.1186\/1471-2121-11-45"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/mi.2016.35","article-title":"Sphingosine-1-Phosphate Receptor-1 (S1p(1)) Is Expressed by Lymphocytes, Dendritic Cells, and Endothelium and Modulated During Inflammatory Bowel Disease","volume":"10","author":"Karuppuchamy","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/nri2400","article-title":"The Alliance of Sphingosine-1-Phosphate and Its Receptors in Immunity","volume":"8","author":"Rivera","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc2875","article-title":"Sphingosine 1-Phosphate and Cancer","volume":"10","author":"Pyne","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15929","DOI":"10.1074\/jbc.M111.230870","article-title":"Ceramide Synthase-Dependent Ceramide Generation and Programmed Cell Death Involvement of Salvage Pathway in Regulating Postmitochondrial Events","volume":"286","author":"Mullen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6352","DOI":"10.1158\/0008-5472.CAN-14-1292","article-title":"Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence","volume":"74","author":"Payne","year":"2014","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1016\/j.bbamem.2006.05.011","article-title":"Ceramide 1-Phosphate\/Ceramide, a Switch between Life and Death","volume":"1758","year":"2006","journal-title":"Biochim. Biophys. Acta-Biomembr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cellsig.2008.11.003","article-title":"Ceramide 1-Phosphate (C1p) Promotes Cell Migration Involvement of a Specific C1p Receptor","volume":"21","author":"Granado","year":"2009","journal-title":"Cell Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.4103\/0366-6999.238135","article-title":"miR-125b-1-3p Exerts Antitumor Functions in Lung Carcinoma Cells by Targeting S1pr1","volume":"131","author":"Zhang","year":"2018","journal-title":"Chin. Med. J."},{"key":"ref_26","first-page":"2346","article-title":"Mirna-125b Inhibits Proliferation and Migration by Targeting Sphk1 in Bladder Cancer","volume":"7","author":"Zhao","year":"2015","journal-title":"Am. J. Transl. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yang, W.W., Wang, A.N., Zhao, C.L., Li, Q.H., Pan, Z.F., Han, X.F., Zhang, C.J., Wang, G.H., Ji, C., and Wang, G.L. (2016). miR-125b Enhances Il-8 Production in Early-Onset Severe Preeclampsia by Targeting Sphingosine-1-Phosphate Lyase 1. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166940"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13233","DOI":"10.1038\/s41598-018-31666-1","article-title":"Sphingosine Kinases Promote Il-17 Expression in Human T Lymphocytes","volume":"8","author":"Barra","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Adamowicz, M., Stukan, I., Milkiewicz, P., Bialek, A., Milkiewicz, M., and Kempinska-Podhorodecka, A. (2022). Modulation of Mismatch Repair and the Socs1\/P53 Axis by Microrna-155 in the Colon of Patients with Primary Sclerosing Cholangitis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094905"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine Storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/01635588709513913","article-title":"The Importance of the Ratio of Lithocholic to Deoxycholic Acid in Large Bowel Carcinogenesis","volume":"9","author":"Owen","year":"1987","journal-title":"Nutr. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1074\/jbc.M805804200","article-title":"Characterization of Enantiomeric Bile Acid-Induced Apoptosis in Colon Cancer Cell Lines","volume":"284","author":"Katona","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.3748\/wjg.v19.i27.4289","article-title":"miR-20b, miR-98, miR-125b-1*, and Let-7e* as New Potential Diagnostic Biomarkers in Ulcerative Colitis","volume":"19","author":"Coskun","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1096\/fj.201600394R","article-title":"Sphingosine-1-Phosphate Phosphatase 2 Promotes Disruption of Mucosal Integrity, and Contributes to Ulcerative Colitis in Mice and Humans","volume":"30","author":"Huang","year":"2016","journal-title":"FASEB J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The Metabolism of Tumors in the Body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1136\/gutjnl-2019-319438","article-title":"Genomic and Transcriptomic Profiling of Carcinogenesis in Patients with Familial Adenomatous Polyposis","volume":"69","author":"Li","year":"2019","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1002\/ibd.20946","article-title":"Fecal Dimeric M2-Pyruvate Kinase (Tumor M2-Pk) in the Differential Diagnosis of Functional and Organic Bowel Disorders","volume":"15","author":"Jeffery","year":"2009","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.clinbiochem.2017.12.007","article-title":"Elevation of Serum Pyruvate Kinase M2 (Pkm2) in Ibd and Its Relationship to Ibd Indices","volume":"53","author":"Almousa","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrm1103","article-title":"Sphingosine-1-Phosphate: An Enigmatic Signalling Lipid","volume":"4","author":"Spiegel","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nrd4099","article-title":"Targeting the Sphingosine-1-Phosphate Axis in Cancer, Inflammation and Beyond","volume":"12","author":"Kunkel","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58247","DOI":"10.18632\/oncotarget.17461","article-title":"Novel Pleiotropic Effects of Bioactive Phospholipids in Human Lung Cancer Metastasis","volume":"8","author":"Schneider","year":"2017","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.biocel.2011.12.019","article-title":"Long Chain Ceramides and Very Long Chain Ceramides Have Opposite Effects on Human Breast and Colon Cancer Cell Growth","volume":"44","author":"Hartmann","year":"2012","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/cjp2.5","article-title":"High Cers5 Expression Levels Associate with Reduced Patient Survival and Transition from Apoptotic to Autophagy Signalling Pathways in Colorectal Cancer","volume":"1","author":"Fitzgerald","year":"2014","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1146\/annurev.physiol.60.1.643","article-title":"Regulation of Ceramide Production and Apoptosis","volume":"60","author":"Kolesnick","year":"1998","journal-title":"Annu. Rev. Physiol."},{"key":"ref_45","first-page":"1437","article-title":"Microrna miR-125b Is a Prognostic Marker in Human Colorectal Cancer","volume":"38","author":"Nishida","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10134","DOI":"10.1038\/s41598-021-89631-4","article-title":"Role of miR-506 in Ulcerative Colitis Associated with Primary Sclerosing Cholangitis","volume":"11","author":"Adamowicz","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1002\/ijc.26167","article-title":"Candidate Driver Genes in Microsatellite-Unstable Colorectal Cancer","volume":"130","author":"Alhopuro","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7921","DOI":"10.1007\/s13277-014-2074-y","article-title":"Decreased Arid1a Expression Facilitates Cell Proliferation and Inhibits 5-Fluorouracil-Induced Apoptosis in Colorectal Carcinoma","volume":"35","author":"Xie","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1016\/j.humpath.2014.04.009","article-title":"Loss of Arid1a Expression in Colorectal Carcinoma Is Strongly Associated with Mismatch Repair Deficiency","volume":"45","author":"Chou","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1097\/PAS.0000000000000554","article-title":"Swi\/Snf Complex-Deficient Undifferentiated\/Rhabdoid Carcinomas of the Gastrointestinal Tract a Series of 13 Cases Highlighting Mutually Exclusive Loss of Smarca4 and Smarca2 and Frequent Co-Inactivation of Smarcb1 and Smarca2","volume":"40","author":"Agaimy","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"945368","DOI":"10.3389\/fcimb.2022.945368","article-title":"The Gut Microbiota-Bile Acid Axis: A Potential Therapeutic Target for Liver Fibrosis","volume":"12","author":"Zhang","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.tiv.2012.12.020","article-title":"Bile Acids in the Colon, from Healthy to Cytotoxic Molecules","volume":"27","author":"Barrasa","year":"2013","journal-title":"Toxicol. Vitr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.mrrev.2004.08.001","article-title":"Bile Acids as Carcinogens in Human Gastrointestinal Cancers","volume":"589","author":"Bernstein","year":"2005","journal-title":"Mutat. Res. Mutat. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:40:45Z","timestamp":1760125245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,24]]},"references-count":53,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119175"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119175","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,24]]}}}