title: TGF-β1-dependent L1CAM expression has an essential role in macrophage-induced apoptosis resistance and cell migration of human intestinal epithelial cells.
abstract: Patients with chronic inflammatory bowel disease (IBD) have an increased risk to develop colorectal cancer (CRC) particularly after long duration of the disease. Chronic inflammation of the intestinal mucosa is characterized by a marked enrichment of immune cells such as macrophages as well as by high expression of cytokines and growth factors including transforming growth factor-beta 1 (TGF-β1). The adhesion molecule L1CAM mediates chemoresistance and migration of tumor cells and is elevated in CRC tissues being associated with metastatic spread and poor prognosis for the patients. In this study, we examine the role of TGF-β1-induced L1CAM expression and macrophages in malignant transformation of intestinal epithelial cells. We demonstrate that TGF-β1 stimulation leads to a Slug-dependent upregulation of L1CAM expression already in the colonic intestinal epithelial cell line NCM460 thereby enhancing cell motility and apoptosis resistance. Accordingly, NCM460 cells acquired a migratory and apoptosis-resistant phenotype if transfected with L1CAM. Immunohistochemistry of colonic biopsies revealed considerable L1CAM expression in intestinal epithelial cells in tissues from IBD patients but not in normal colonic tissues. Moreover, L1CAM expression increased with duration of disease being associated with the presence of CD33+ macrophages. Coculture with macrophages generated from monocyte colony-stimulating factor (MCSF)-treated monocytes led to the upregulation of Slug and L1CAM in NCM460 cells thereby elevating cell motility and apoptosis resistance. Pharmacological inhibition of TGF-β1 signalling abolished expression of Slug and L1CAM in cocultured NCM460 cells resulting in decreased cell migration and apoptosis resistance. In conclusion, these data provide new insights into the mechanisms by which IBD promotes malignant transformation of intestinal epithelial cells and underscore the role of L1CAM and macrophages in this scenario.
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, Kiel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
authors.forename: B
authors.initials: B
authors.lastname: Struck
authors.forename: E-M
authors.initials: EM
authors.lastname: Feldmann
authors.forename: F
authors.initials: F
authors.lastname: Bergmann
authors.forename: E
authors.initials: E
authors.lastname: Grage-Griebenow
authors.forename: C
authors.initials: C
authors.lastname: Geismann
authors.forename: S
authors.initials: S
authors.lastname: Ehlers
authors.forename: P
authors.initials: P
authors.lastname: Altevogt
authors.forename: S
authors.initials: S
authors.lastname: Sebens
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000096:biosynthesis; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D048055:Mitogen-Activated Protein Kinase 8