Oxytocin alleviated colitis and colitis-associated colorectal tumorigenesis by targeting fucosylated MUC2

Colon cancer is commonly regarded as hormone-independent. However, there have been reports suggesting the involvement of sex hormones in colon cancer development. Nevertheless, the role of hormones from the hypothalamus-hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both colitis and CAC patients. To investigate further, we generated mice with an intestinal epithelium cell (IEC)-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and DSS/Azoxymethane (AOM)-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate MUC2 maturation through B3GNT7-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the administration of oxytocin significantly alleviated tumor burden. Hence, our study unveils oxytocin’s promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.

[1]  Jianxin Zhao,et al.  L-Fucose increases the fucosylation of colorectal cancer cells via promoting the accumulation of serine. , 2023, Food & function.

[2]  N. Schultz,et al.  Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers , 2023, Nature Communications.

[3]  Huimin Qi,et al.  Hormone supply to the pituitary gland: A comprehensive investigation of female-related tumors (Review) , 2022, International journal of molecular medicine.

[4]  C. Dai,et al.  MUC2 and related bacterial factors: Therapeutic targets for ulcerative colitis , 2021, EBioMedicine.

[5]  Jennifer J. Kohler,et al.  Interleukin-22 regulates B3GNT7 expression to induce fucosylation of glycoproteins in intestinal epithelial cells , 2021, The Journal of biological chemistry.

[6]  I. Gut,et al.  The ulcerative colitis-associated gene FUT8 regulates the quantity and quality of secreted mucins , 2021, bioRxiv.

[7]  D. Quintana,et al.  Oxytocin’s dynamic role across the lifespan , 2021, Aging brain.

[8]  Yunyun Han,et al.  Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice , 2021, eLife.

[9]  Rong Lin,et al.  Exogenous l‐fucose protects the intestinal mucosal barrier depending on upregulation of FUT2‐mediated fucosylation of intestinal epithelial cells , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  Jingxin Li,et al.  Oxytocin signalling in dendritic cells regulates immune tolerance in the intestine and alleviates DSS-induced colitis. , 2021, Clinical science.

[11]  Ting Zhang,et al.  Prognostic role of oxytocin receptor in colon adenocarcinoma , 2021, Open medicine.

[12]  A. Bitto,et al.  Growth hormone-releasing hormone (GHRH) deficiency promotes inflammation-associated carcinogenesis. , 2019, Pharmacological research.

[13]  Yong Feng,et al.  Oxytocin Inhibition of Metastatic Colorectal Cancer by Suppressing the Expression of Fibroblast Activation Protein-α , 2019, Front. Neurosci..

[14]  Jingxin Li,et al.  Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis. , 2019, Clinical science.

[15]  Shengyu Yang,et al.  The Diverse Contributions of Fucose Linkages in Cancer , 2019, Cancers.

[16]  A. Jakab,et al.  Hormone Replacement Therapy in Cancer Survivors – Review of the Literature , 2019, Pathology & Oncology Research.

[17]  A. Nakagawara,et al.  Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma , 2016, Journal of Hematology & Oncology.

[18]  S. Markowitz,et al.  Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma. , 2016, Gastroenterology.

[19]  J. Braun,et al.  Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. , 2016, Gastroenterology.

[20]  Lai-Xi Wang,et al.  Mammalian α-1,6-Fucosyltransferase (FUT8) Is the Sole Enzyme Responsible for the N-Acetylglucosaminyltransferase I-independent Core Fucosylation of High-mannose N-Glycans* , 2016, The Journal of Biological Chemistry.

[21]  Jingxin Li,et al.  Oxytocin evokes a pulsatile PGE2 release from ileum mucosa and is required for repair of intestinal epithelium after injury , 2015, Scientific Reports.

[22]  O. Martínez-Augustin,et al.  Intestinal Inflammation and Mucosal Barrier Function , 2014, Inflammatory bowel diseases.

[23]  M. Welch,et al.  Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[24]  Lung-Chih Yu,et al.  Suppression of B3GNT7 gene expression in colon adenocarcinoma and its potential effect in the metastasis of colon cancer cells. , 2014, Glycobiology.

[25]  S. Grivennikov.  Inflammation and colorectal cancer: colitis-associated neoplasia , 2012, Seminars in Immunopathology.

[26]  H. Kawashima.  Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer. , 2012, Biological & pharmaceutical bulletin.

[27]  Stuart M Haslam,et al.  Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome. , 2012, Nature chemical biology.

[28]  Min Zhang,et al.  Oxytocin hyperpolarizes cultured duodenum myenteric intrinsic primary afferent neurons by opening BKCa channels through IP3 pathway , 2012, Journal of neurochemistry.

[29]  H. Tamir,et al.  Expression and developmental regulation of oxytocin (OT) and oxytocin receptors (OTR) in the enteric nervous system (ENS) and intestinal epithelium , 2009, The Journal of comparative neurology.

[30]  Markus F Neurath,et al.  An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression , 2007, Nature Protocols.

[31]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[32]  J. Meijerink,et al.  Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. , 2006, Gastroenterology.

[33]  C. Rogers,et al.  Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus , 2002, The Journal of cell biology.

[34]  G. Gimpl,et al.  The oxytocin receptor system: structure, function, and regulation. , 2001, Physiological reviews.

[35]  N. Sala,et al.  Oxytocin reproducing reflex milk ejection in lactating women. , 1974, Journal of applied physiology.