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L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

Oncogene volume 29, pages 4766–4778 (2010)Cite this article

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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-κB, which was abolished by L1CAM knockdown. We showed that the expression of IL-1β was selectively upregulated by L1-FL, and increased IL-1β levels were instrumental for sustained NF-κB activation. IL-1β production and NF-κB activation were abolished by knockdown of α5-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&!minus;-binding integrins, leading to sustained NF-κB activation by IL-1β production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells.

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Abbreviations

ADAM:

A Disintegrin And Metalloprotease

IL-1β:

Interleukin 1 beta

L1CAM:

L1 cell adhesion molecule

L1-FL:

L1CAM full length

L1ecto:

the ectodomain of L1CAM

L1cyt:

the cytoplasmic fragment of L1CAM

L1-RGE:

human L1CAM with mutations of RGD to RGE

NF-κB:

nuclear factor kappa B

PDAC:

pancreatic ductal adenocarcinoma

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Acknowledgements

We acknowledge the competent help of Dr Alex Stoeck (University of Michigan, Ann Arbor) in retroviral expression in the early phase of the study. We also thank Ramona Straub and Dagmar Leisner for excellent technical assistance. This study was supported by grants from Deutsche Krebshilfe (Schwerpunktprogramm: Invasion and Migration), the Deutsche Forschungsgemeinschaft project nr. SE-1831/2-1 to S.S. and the EU-FP6 framework program OVCAD project nr. PE-14034 to PA. Further financial support was received from a collaborative research grant from Medigene Inc. (Munich) to PA.

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Authors and Affiliations

  1. Translational Immunology, German Cancer Research Center, Heidelberg, Germany

    H Kiefel, S Bondong, N Erbe-Hoffmann, J Hazin, S Riedle, J Wolf, M Pfeifer & P Altevogt

  2. Clinic for Internal Medicine, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus, University of Kiel, Kiel, Germany

    A Arlt, H Schäfer & S Sebens Müerköster

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  1. H Kiefel
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Correspondence to P Altevogt.

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Kiefel, H., Bondong, S., Erbe-Hoffmann, N. et al. L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression. Oncogene 29, 4766–4778 (2010). https://doi.org/10.1038/onc.2010.230

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