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TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

Oncogene volume 30, pages 3049–3061 (2011)Cite this article

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Abstract

Tumor protein 53 induced nuclear protein 1 (TP53INP1) is a p53 target gene that induces cell growth arrest and apoptosis by modulating p53 transcriptional activity. TP53INP1 interacts physically with p53 and is a major player in the p53-driven oxidative stress response. Previously, we demonstrated that TP53INP1 is downregulated in an early stage of pancreatic cancerogenesis and when restored is able to suppress pancreatic tumor development. TP53INP1 downregulation in pancreas is associated with an oncogenic microRNA miR-155. In the present work, we studied the effects of TP53INP1 on cell migration. We found that TP53INP1 inactivation correlates with increased cell migration both in vivo and in vitro. The impact of TP53INP1 expression on cell migration was studied in different cellular contexts: mouse embryonic fibroblast and different pancreatic cancer cell lines. Its expression decreases cell migration by the transcriptional downregulation of secreted protein acidic and rich in cysteine (SPARC). SPARC is a matrix cellular protein, which governs diverse cellular functions and has a pivotal role in regulating cell-matrix interactions, cellular proliferation and migration. SPARC was also showed to be upregulated in normal pancreas and in pancreatic intraepithelial neoplasia lesions in a pancreatic adenocarcinoma mouse model only in the TP53INP1-deficient animals. This novel TP53INP1 activity on the regulation of SPARC expression could explain in part its tumor suppressor function in pancreatic adenocarcinoma by modulating cellular spreading during the metastatic process.

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Abbreviations

CM:

Culture Medium

CTL:

Control

ECM:

Extracellular Matrix

FN1:

fibronectin-1

GFP:

Green Fluorescent Protein

IHC:

immunohistochemistry

MEF:

Mouse Embryonic Fibroblasts

PDAC:

Pancreatic Ductal Adenocarcinoma

PanIN:

Pancreatic Intraepithelial Neoplasia

Pdx1:

Pancreatic and duodenal homeobox 1

PonA:

Ponasterone A

PLL:

Polylysine

TCL:

Total Cellular Extract

Vn:

vitronectin

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Acknowledgements

This work was supported in part by Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique and grants from the Institut National du Cancer, La Ligue Nationale Contre le Cancer, Association pour la Recherche sur le Cancer and the Agence Nationale de la Recherche. M Seux was supported by Association pour la Recherche sur le Cancer and S Peuget by the Club Franiçais du Pancréas and Ministèère de la Recherche et de la Technologie. Authors acknowledge Tony George JACOB and Antoine Baud for critically reading the manuscript and helpful comments respectively.

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Authors and Affiliations

  1. INSERM, U624 ‘Stress cellulaire’, Marseille, France

    M Seux, S Peuget, L Pouyet, P N'Guessan, S Garcia, J L Iovanna, A Carrier & N J Dusetti

  2. Aix-Marseille Université, Campus de Luminy, Marseille, France

    M Seux, S Peuget, L Pouyet, P N'Guessan, S Garcia, J L Iovanna, A Carrier & N J Dusetti

  3. INSERM U911, CRO2, Aix-Marseille Université, Marseille, France

    M P Montero, C Siret, V Rigot, E Pellegrino & F André

  4. INSERM U858/I2MR, IFR150, Université de Toulouse, Toulouse, France

    P Clerc, V Gigoux & M Dufresne

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  1. M Seux
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Correspondence to N J Dusetti.

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Seux, M., Peuget, S., Montero, M. et al. TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression. Oncogene 30, 3049–3061 (2011). https://doi.org/10.1038/onc.2011.25

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