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
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 ca...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| author | Joanna Abramczyk Malgorzata Milkiewicz Bartosz Hula Piotr Milkiewicz Agnieszka Kempinska-Podhorodecka |
| author_facet | Joanna Abramczyk Malgorzata Milkiewicz Bartosz Hula Piotr Milkiewicz Agnieszka Kempinska-Podhorodecka |
| author_sort | Joanna Abramczyk |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T03:06:27Z |
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| language | English |
| last_indexed | 2024-03-11T03:06:27Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3cff057bb4ee4923ad15f6c4540c32242023-11-18T07:55:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411917510.3390/ijms24119175The Role of hsa-miR-125b-5p Interaction with S1P/Ceramide Axis in the Potential Development of Inflammation-Associated Colon Cancer in Primary Sclerosing CholangitisJoanna Abramczyk0Malgorzata Milkiewicz1Bartosz Hula2Piotr Milkiewicz3Agnieszka Kempinska-Podhorodecka4Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, PolandDepartment of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, PolandDepartment of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, PolandLiver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, PolandDepartment of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, PolandPrimary 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.https://www.mdpi.com/1422-0067/24/11/9175microRNAmicrosatellite instabilitycholestatic liver diseaseinflammatory bowel diseasecolorectal cancer |
| spellingShingle | Joanna Abramczyk Malgorzata Milkiewicz Bartosz Hula Piotr Milkiewicz Agnieszka Kempinska-Podhorodecka 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 International Journal of Molecular Sciences microRNA microsatellite instability cholestatic liver disease inflammatory bowel disease colorectal cancer |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | role of hsa mir 125b 5p interaction with s1p ceramide axis in the potential development of inflammation associated colon cancer in primary sclerosing cholangitis |
| topic | microRNA microsatellite instability cholestatic liver disease inflammatory bowel disease colorectal cancer |
| url | https://www.mdpi.com/1422-0067/24/11/9175 |
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