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The impact of microRNA expression on cellular proliferation

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Abstract

As an important class of non-coding regulatory RNAs, microRNAs (miRNAs) play a key role in a range of biological processes. These molecules serve as post-transcriptional regulators of gene expression and their regulatory activity has been implicated in disease pathophysiology and pharmacological traits. We sought to investigate the impact of miRNAs on cellular proliferation to gain insight into the molecular basis of complex traits that depend on cellular growth, including, most prominently, cancer. We examined the relationship between miRNA expression and intrinsic cellular growth (iGrowth) in the HapMap lymphoblastoid cell lines derived from individuals of different ethnic backgrounds. We found a substantial enrichment for miRNAs (53 miRNAs, FDR < 0.05) correlated with cellular proliferation in pooled CEU (Caucasian of northern and western European descent) and YRI (individuals from Ibadan, Nigeria) samples. Specifically, 119 miRNAs (59 %) were significantly correlated with iGrowth in YRI; of these miRNAs, 18 were correlated with iGrowth in CEU. To gain further insight into the effect of miRNAs on cellular proliferation in cancer, we showed that over-expression of miR-22, one of the top iGrowth-associated miRNAs, leads to growth inhibition in an ovarian cancer cell line (SKOV3). Furthermore, over-expression of miR-22 down-regulates the expression of its target genes (MXI1 and SLC25A37) in this ovarian cancer cell line, highlighting an miRNA-mediated regulatory network potentially important for cellular proliferation. Importantly, our study identified miRNAs that can be used as molecular targets in cancer therapy.

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Abbreviations

miRNA:

microRNA

iGrowth:

Intrinsic cellular growth

LCLs:

Lymphoblastoid cell lines

CEU:

Centre d’Etude du Polymorphisme Humain (CEPH) people from Utah, USA

YRI:

Yoruba people from Ibadan, Nigeria

MEM:

Mixed effects model averaging

FDR:

False discovery rate

DAVID:

Database for Annotation, Visualization and Integrated Discovery

GO:

Gene ontology

DOHH:

Deoxyhypusine hydroxylase

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Acknowledgments

We are grateful for the excellent technical support provided by Pharmacogenomics of Anti-cancer Agent Research (PAAR) group cell line core. This study was supported by National Institute of Health/National Cancer Institute grant (R21 CA139278) and by National Institute of Health/National Institute of General Medical Sciences grant (UO1GM61393). RSH also received support from National Institute of Health/National Institute of General Medical Sciences grant (K08GM089941), Circle of Service Foundation Early Career Investigator award, University of Chicago Cancer Center Support Grant (#P30 CA14599), Breast Cancer SPORE Career Development Award (CA125183) a Conquer Cancer Foundation of ASCO Translational Research Professorship award In Memory of Merrill J. Egorin, MD, and pilot grant from National Institute of Health/National Center Advancing Translational Sciences grant (UL1RR024999).

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Authors and Affiliations

  1. Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 900 E 57th Street, KCBD, Chicago, IL, 60637, USA

    Divya Lenkala, Bonnie LaCroix, Paul Geeleher & R. Stephanie Huang

  2. Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA

    Eric R. Gamazon

  3. Department of Health Studies, The University of Chicago, Chicago, IL, 60637, USA

    Hae Kyung Im

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  1. Divya Lenkala
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  2. Bonnie LaCroix
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  3. Eric R. Gamazon
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  4. Paul Geeleher
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  5. Hae Kyung Im
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  6. R. Stephanie Huang
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Correspondence to R. Stephanie Huang.

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Lenkala, D., LaCroix, B., Gamazon, E.R. et al. The impact of microRNA expression on cellular proliferation. Hum Genet 133, 931–938 (2014). https://doi.org/10.1007/s00439-014-1434-4

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