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Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Oncogene volume 26, pages 2082–2094 (2007)Cite this article

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the α6β4 integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

PDAC:

pancreatic ductal adenocarcinoma

PN:

periostin

rPN:

recombinant periostin protein

PMA:

Phorbol 12-myristate 13-acetate

FGFα:

acidic Fibroblast Growth Factor^TGFβ, Transforming Growth Factor beta

PI:

propidium iodine

QRT-PCR:

quantitative real-time PCR

ISH:

In situ mRNA hybridization

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Acknowledgements

We thank Dr John F Marshall for kindly providing the amphotropic retrovirus expressing human β3 integrin cDNA (Centre for Tumour Biology, Institute of Cancer and the CR-UK Clinical Centre, London, UK). This work was supported by a programme grant from Cancer Research UK (C355/A6253) and CORE programme grant.

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Authors and Affiliations

  1. Centre for Molecular Oncology, Institute of Cancer and the CR-UK Clinical Centre, Barts and The London, Charterhouse Square, London, UK

    P Baril, R Gangeswaran, P C Mahon, K Caulee, T Harada, T Crnogorac-Jurcevic & N R Lemoine

  2. Centre for Tumour Biology, Institute of Cancer and the CR-UK Clinical Centre, Barts and The London, Charterhouse Square, London, UK

    H M Kocher

  3. Department of Medicine/Division of Hematology-Oncology, UCLA David Geffen School of Medicine Los Angeles, Los Angeles, CA, USA

    M Zhu

  4. Clinic for General Surgery and Thoracic Surgery, University of Kiel, Kiel, Germany

    H Kalthoff

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  1. P Baril
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Correspondence to N R Lemoine.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Baril, P., Gangeswaran, R., Mahon, P. et al. Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway. Oncogene 26, 2082–2094 (2007). https://doi.org/10.1038/sj.onc.1210009

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