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  • 1
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; human ; tumor growth ; SYSTEM ; SITE ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; LINES ; MICE ; LIGAND ; prognosis ; DOMAIN ; BINDING ; BIOLOGY ; CELL-LINES ; MOLECULE ; ALPHA ; antibodies ; antibody ; MUTANT ; NERVOUS-SYSTEM ; METASTASIS ; NUDE-MICE ; CELL-LINE ; BETA ; ADHESION ; MIGRATION ; INTEGRIN ; CARCINOMAS ; HOMOPHILIC BINDING ; L1 ; MALIGNANT-MELANOMA ; NEURITE OUTGROWTH ; ADHESION MOLECULE ; CELL-ADHESION MOLECULE ; signaling ; ONCOLOGY ; RE ; TUMOR-GROWTH ; cell adhesion ; gene regulation ; INTEGRINS ; cell migration ; RGD ; NUCLEAR ; USA ; MOTILITY ; OVARIAN-CARCINOMA CELLS ; L1CAM ; CELL MOTILITY ; CELL BIOLOGY ; CELL ADHESION MOLECULE
    Abstract: L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system. L1 is also overexpressed in a variety of human carcinomas and is associated with bad prognosis. In carcinoma cell lines L1 augments cell motility and metastasis, tumor growth in nude mice and induces expression of L1-dependent genes. It is not known whether L1-signaling requires ligand binding. The RGD motif in the sixth Ig domain of L1 is a binding site for integrins. In the present study we analyzed the role of RGDs in L1-signaling using site-directed mutagenesis combined with antibody blocking studies. We observed that L1-RGE expressing HEK293 cells showed reduced cell-cell binding, cell motility, invasiveness and tumor growth in NOD/SCID mice. The RGE-mutation impaired L1-dependent gene regulation and antibodies to alpha v beta 5 integrin had similar effects. Mutant L1 was unable to translocate to the nucleus. our findings highlight the importance of the RGD site in L1 for human tumors and suggest that nuclear signaling of L1 is dependent on integrins. (c) 2008 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18555990
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; CELL ; Germany ; human ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; LINES ; ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; INDUCTION ; TISSUES ; mechanisms ; C-JUN ; CELL-LINES ; MOLECULE ; PROGRESSION ; immunohistochemistry ; PROMOTER ; UP-REGULATION ; BETA ; ADHESION ; MIGRATION ; TRANSFORMATION ; MALIGNANT TRANSFORMATION ; PHENOTYPE ; adenocarcinoma ; GROWTH-FACTOR-BETA ; ADHESION MOLECULE ; INSIGHTS ; cell lines ; pancreatic cancer ; chronic pancreatitis ; MAP KINASES ; TGF-BETA-1 ; chemoresistance ; FACTOR-BETA ; PANCREATIC-CANCER ; TUMOR-GROWTH ; DUCTAL ADENOCARCINOMA ; TUMORIGENESIS ; TGF-BETA ; ADHESION MOLECULE L1 ; USA ; MOTILITY ; OVARIAN-CARCINOMA CELLS ; EPITHELIAL-MESENCHYMAL TRANSITION ; L1CAM ; pancreatic ductal adenocarcinoma ; KINASE ACTIVATION ; INVESTIGATE ; TRANSCRIPTION-FACTOR
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is thought to originate front ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic fissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-beta 1 (TGF-beta 1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in mono-cultured H6c7 cells after administration of exogenous TGF-beta 1. Both TGF-beta 1- and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH2-terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, anti its knockdown abrogated the TGF-beta 1- anti PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-beta 1-induced L1CAM expression anti the resulting phenotype could be verified in the TGF-beta 1-responsive PDAC cell lines Colo357 and Pancl. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis. [Cancer lies 2009:69(10):,1517-26]
    Type of Publication: Journal article published
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  • 3
    Abstract: L1 cell adhesion molecule (L1CAM) overexpression is often associated with bad prognosis in various human carcinomas. Recent studies also suggest a role of L1CAM in pancreatic ductal adenocarcinomas (PDAC). To further address its contribution, we expressed functional domains of L1CAM in PT45-P1 PDAC cells. We found that L1CAM that is full length (L1-FL), but neither the soluble ectodomain (L1ecto) nor the cytoplasmic part (L1cyt), could enhance cell proliferation or tumour growth in mice. Expression of L1-FL resulted in constitutive activation of NF-kappa B, which was abolished by L1CAM knockdown. We showed that the expression of IL-1 beta was selectively upregulated by L1-FL, and increased IL-1 beta levels were instrumental for sustained NF-kappa B activation. IL-1 beta production and NF-kappa B activation were abolished by knockdown of alpha 5-integrin and integrin-linked kinase, but insensitive to depletion of L1CAM cleavage proteinases. Supporting these data, PT45-P1 cells transduced with an L1CAM mutant deficient in integrin binding (L1-RGE) did not support the described L1-FL functions. Our results suggest that membranous L1CAM interacts with RGD-binding integrins, leading to sustained NF-kappa B activation by IL-1 beta production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells. Oncogene (2010) 29, 4766-4778; doi:10.1038/onc.2010.230; published online 14 June 2010
    Type of Publication: Journal article published
    PubMed ID: 20543863
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