Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine
| Autor: | Shaoping Wu, Yong-Guo Zhang, Ishita Chatterjee, Jun Sun, Yinglin Xia, Rong Lu, David Zhou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Carcinogenesis medicine.disease_cause Calcitriol receptor IEC intestinal epithelial cell chemistry.chemical_compound 0302 clinical medicine PCR polymerase chain reaction Conditional gene knockout polycyclic compounds Host–Bacterial Interactions Vitamin D STAT3 Original Research Cancer 0303 health sciences biology ESI electrospray ionization STAT digestive oral and skin physiology Gastroenterology Lcn-2 lipocalin 2 JAK-STAT signaling pathway CRC colon rectal cancer 3. Good health ChIP chromatin immunoprecipitation Intestines 030220 oncology & carcinogenesis LPS lipopolysaccharide VDR vitamin D receptor 030211 gastroenterology & hepatology lipids (amino acids peptides and proteins) musculoskeletal diseases SDS sodium dodecyl sulfate PCNA proliferating cell nuclear antigen Jak/STAT Janus kinase/signal transducer and activator of transcription stat 03 medical and health sciences medicine Humans AOM/DSS azoxymethane dextran sodium sulfate lcsh:RC799-869 030304 developmental biology VDR Inflammation KO knockout Hepatology Azoxymethane UPLC-MS/MS ultra high-performance liquid chromatography–tandem mass spectroscopy medicine.disease Gastrointestinal Microbiome 030104 developmental biology 1 25(OH)2D3 1α 25-dihydroxy vitamin D3 chemistry Colonoids STAT protein Cancer research biology.protein Dysbiosis Receptors Calcitriol lcsh:Diseases of the digestive system. Gastroenterology Microbiome Nuclear Receptor Janus kinase |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 4, Pp 729-746 (2020) |
| ISSN: | 2352-345X |
| Popis: | BackgroundVitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the JAK/STAT pathway in tumorigenesis. To test our hypothesis, we used an azoxymethane/Dextran Sulfate Sodium-induced cancer model in intestinal VDR conditional knockout (VDRΔIEC) mice, cell cultures, stem-cell derived colonoids, and human colon cancer samples.ResultsVDRΔIEC mice have higher numbers of tumors with location shifted from distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDRΔIEC mice showed elevated secondary bile acids, consistent with the observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDRΔIEC mice activate the STAT3 activation in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in respond to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3.ConclusionWe provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target — microbiome and VDR for prevention of cancer. |
| Databáze: | OpenAIRE |
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