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MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers

Oncogene volume 27, pages 6667–6678 (2008)Cite this article

Abstract

Suppression of annexin A1 (ANXA1), a mediator of apoptosis and inhibitor of cell proliferation, is well documented in various cancers but the underlying mechanism remains unknown. We investigated whether decreased ANXA1 expression was mediated by microRNAs (miRNAs), which are small, non-coding RNAs that negatively regulate gene expression. Using Sanger miRBase, we identified miR-584, miR-196a and miR-196b as potential miRNAs targeting ANXA1. Only miRNA-196a showed significant inverse correlation with ANXA1 mRNA levels in 12 cancer cell lines of esophageal, breast and endometrial origin (Pearson's correlation −0.66, P=0.019), identifying this as the candidate miRNA targeting ANXA1. Inverse correlation was also observed in 10 esophageal adenocarcinomas (Pearson's correlation −0.64, P=0.047). Analysis of paired normal/tumor tissues from additional 10 patients revealed an increase in miR-196a in the cancers (P=0.003), accompanied by a decrease in ANXA1 mRNA (P=0.004). Increasing miR-196a levels in cells by miR-196a mimics resulted in decreased ANXA1 mRNA and protein. In addition, miR-196a mimics inhibited luciferase expression in luciferase plasmid reporter that included predicted miR-196a recognition sequence from ANXA1 3′-untranslated region confirming that miR-196a directly targets ANXA1. miR-196a promoted cell proliferation, anchorage-independent growth and suppressed apoptosis, suggesting its oncogenic potential. This study demonstrated a novel mechanism of post-transcriptional regulation of ANXA1 expression and identified miR-196a as a marker of esophageal cancer.

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Acknowledgements

We thank Dawn Chalaire for critical editing of the manuscript and James M Gilbert and Kim-Anh Vu for assistance with preparation of the manuscript and illustrations. We also thank Drs Raju, Izzo and Liu of MD Anderson Cancer Center for providing the cell lines used in the study.This study was supported by Goodwin Fund for Target Molecular Diagnosis and Institutional Research Grant (CT Albarracin), NIH 1P50CA098258-01, SPORE in Uterine Cancer (RR Broaddus).

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  1. R R Singh, M G Luthra and Y X Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R Luthra, R R Singh, C Hannah, A M Romans & B A Barkoh

  2. Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M G Luthra, Y X Li, D M Maru, R R Broaddus, A Rashid & C T Albarracin

  3. Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S S Chen

  4. Department of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Ensor

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  1. R Luthra
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Correspondence to R Luthra.

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Luthra, R., Singh, R., Luthra, M. et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene 27, 6667–6678 (2008). https://doi.org/10.1038/onc.2008.256

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