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Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions

International Journal of Colorectal Disease volume 28, pages 751–766 (2013)Cite this article

Abstract

Purpose

Inverse correlations of apolipoprotein D (ApoD) expression with tumor growth have been shown, therefore proposing ApoD as a good prognostic marker for diverse cancer types, including colorectal cancer (CRC). Besides, ApoD expression is boosted upon oxidative stress (OS) in many pathological situations. This study aims at understanding the role of ApoD in the progression of human CRC.

Methods

Samples of CRC and distant normal tissue (n = 51) were assayed for levels of lipid peroxidation, expression profile of OS-dependent genes, and protein expression. Three single-nucleotide polymorphisms in the ApoD gene were analyzed (n = 139), with no significant associations found. Finally, we assayed the effect of ApoD in proliferation and apoptosis in the CRC HT-29 cell line.

Results

In CRC, lipid peroxides increase while ApoD messenger RNA and protein decrease through tumor progression, with a prominent decrease in stage I. In normal mucosa, ApoD protein is present in lamina propia and enteroendocrine cells. In CRC, ApoD expression is heterogeneous, with low expression in stromal cells commonly associated with high expression in the dysplastic epithelium. ApoD promoter is basally methylated in HT-29 cells but retains the ability to respond to OS. Exogenous addition of ApoD to HT-29 cells does not modify proliferation or apoptosis levels in control conditions, but it promotes apoptosis upon paraquat-induced OS.

Conclusion

Our results show ApoD as a gene responding to OS in the tumor microenvironment. Besides using ApoD as marker of initial stages of tumor progression, it can become a therapeutic tool promoting death of proliferating tumor cells suffering OS.

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Acknowledgments

We thank Drs. J. Herreros and B. Velayos for their help in patient recruitment and sample collection. We thank M. Ruiz, N. García, M. del Caño, and A. Pérez for their helpful discussions. We thank Dr. A.S. Peña for his insight and comments on the manuscript.

Grant support

This work has been supported by grants to M.D.G. and D.S. (Ministerio de Educación y Ciencia (MEC), Spain, grant BFU2005-00522; Junta de Castilla y León (JCyL), grant VA049A05; and Ministerio de Ciencia e Innovación (MICINN), grant BFU2008-01170); and to R.B. (JCyL, GRS/278/A/08).

Disclosure of potential conflicts of interest

Authors declare no conflict of interest exists in relation to the content of this manuscript. Neither the author’s institutions nor the funding agencies had a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Affiliations

  1. Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid–CSIC, c/ Sanz y Forés 3, 47003, Valladolid, Spain

    Raquel Bajo-Grañeras, Maria D. Ganfornina & Diego Sanchez

  2. Hospital Clínico Universitario de Valladolid, Valladolid, Spain

    Jesús Crespo-Sanjuan, Rosa M. García-Centeno, José Antonio Garrote-Adrados, Manuel García-Tejeiro, Beatriz Aguirre-Gervás, María D. Calvo-Nieves & Rosa Bustamante

  3. Departamento de Genética, Universidad de Sevilla, Sevilla, Spain

    Gabriel Gutierrez

Authors
  1. Raquel Bajo-Grañeras
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  2. Jesús Crespo-Sanjuan
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  6. Manuel García-Tejeiro
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  10. Maria D. Ganfornina
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  11. Diego Sanchez
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Corresponding author

Correspondence to Diego Sanchez.

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MDG and DS contributed equally to this work.

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Bajo-Grañeras, R., Crespo-Sanjuan, J., García-Centeno, R.M. et al. Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions. Int J Colorectal Dis 28, 751–766 (2013). https://doi.org/10.1007/s00384-012-1616-2

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Keywords

  • Lipocalin
  • Lipid peroxidation
  • Apoptosis
  • Predictive marker
  • DNA methylation
  • Colorectal cancer stages