Oncotarget

Research Papers:

MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1

Radhakrishnan Vishnubalaji, Rimi Hamam, Shijun Yue, Omar Al-Obeed, Moustapha Kassem, Fei-Fei Liu, Abdullah Aldahmash and Nehad M. Alajez _

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Oncotarget. 2016; 7:35789-35802. https://doi.org/10.18632/oncotarget.8937

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Abstract

Radhakrishnan Vishnubalaji1, Rimi Hamam1, Shijun Yue2, Omar Al-Obeed3, Moustapha Kassem1,4,5, Fei-Fei Liu2, Abdullah Aldahmash1,6 and Nehad M. Alajez1

1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia

2 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

3 Colorectal Research Center, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia

4 KMEB, Department of Endocrinology, University of Southern Denmark, Odense, Denmark

5 Danish Stem Cell Center (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark

6 Prince Naif Health Research Center, King Saud University, Riyadh, Kingdom of Saudi Arabia

Correspondence to:

Nehad M. Alajez, email:

Keywords: colorectal cancer, miR-320, SOX4, FOXM1, FOXQ1

Received: December 16, 2015 Accepted: April 12, 2016 Published: April 22, 2016

Abstract

Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide. Delineating the molecular mechanisms leading to CRC development and progression, including the role of microRNAs (miRNAs), are currently being unravelled at a rapid rate. Here, we report frequent downregulation of the microRNA miR-320 family in primary CRC tissues and cell lines. Lentiviral-mediated re-expression of miR-320c (representative member of the miR-320 family) inhibited HCT116 CRC growth and migration in vitro, sensitized CRC cells to 5-Fluorouracil (5-FU), and inhibited tumor formation in SCID mice. Global gene expression analysis in CRC cells over-expressing miR-320c, combined with in silico prediction identified 84 clinically-relevant potential gene targets for miR-320 in CRC. Using a series of biochemical assays and functional validation, SOX4, FOXM1, and FOXQ1 were validated as novel gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients’ specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression levels of this gene panel (SOX4, FOXM1, and FOXQ1) in The Cancer Genome Atlas (TCGA) colorectal cancer data set (319 patients) revealed significantly poor disease-free survival in patients with elevated expression of this gene panel (P-Value: 0.0058). Collectively, our data revealed a novel role for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC.


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