title: EMT-associated up-regulation of L1CAM provides insights into L1CAM-mediated integrin signalling and NF-κB activation.
abstract: Expression of L1 cell adhesion molecule (L1CAM) is associated with poor prognosis in a variety of human carcinomas including breast, ovarian and pancreatic ductal adenocarcinoma (PDAC). Recently we reported that L1CAM induces sustained nuclear factor kappa B (NF-κB) activation by augmenting the autocrine production of interleukin 1 beta (IL-1β), a process dependent on interaction of L1CAM with integrins. In the present study, we demonstrate that transforming growth factor β1 (TGF-β1) treatment of breast carcinoma (MDA-MB231) and PDAC (BxPc3) cell lines induces an EMT (epithelial to mesenchymal transition)-like phenotype and leads to the expression of L1CAM. In MDA-MB231 cells, up-regulation of L1CAM augmented expression of IL-1β and NF-κB activation, which was reversed by depletion of L1CAM, L1CAM-binding membrane cytoskeleton linker protein ezrin, β1-integrin or focal adhesion kinase (FAK). Over-expression of L1CAM not only induced NF-κB activation but also mediated the phosphorylation of FAK and Src. Phosphorylation was not induced in cells expressing a mutant form of L1CAM (L1-RGE) devoid of the integrin-binding site. FAK- and Src-phosphorylation were inhibited by knock-down of various components of the integrin signalling pathway such as β1- and α5-integrins, integrin-linked kinase (ILK), FAK and the phosphoinositide 3-kinase (PI3K) subunit p110β. In summary, these results reveal that during EMT, L1CAM promotes IL-1β expression through a process dependent on integrin signalling and supports a motile and invasive tumour cell phenotype. We also identify important novel downstream effector molecules of the L1CAM-integrin signalling crosstalk that help to understand the molecular mechanisms underlying L1CAM-promoted tumour progression.
authors: German Cancer Research CenterIm Neuenheimer Feld 280, Heidelberg, Germany.
authors: Helena
authors: H
authors: Kiefel
authors: Sandra
authors: S
authors: Bondong
authors: Marco
authors: M
authors: Pfeifer
authors: Uwe
authors: U
authors: Schirmer
authors: Natalie
authors: N
authors: Erbe-Hoffmann
authors: Heiner
authors: H
authors: Schäfer
authors: Susanne
authors: S
authors: Sebens
authors: Peter
authors: P
authors: Altevogt
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis*; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019012:Integrin beta1; D053583:Interleukin-1beta; D016328:NF-kappa B; D039842:Neural Cell Adhesion Molecule L1; D053773:Transforming Growth Factor beta1; D000099149:Ezrin