MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1.
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.
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Radhakrishnan
R
Vishnubalaji
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Rimi
R
Hamam
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Shijun
S
Yue
Colorectal Research Center, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Omar
O
Al-Obeed
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.|KMEB, Department of Endocrinology, University of Southern Denmark, Odense, Denmark.|Danish Stem Cell Center (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Moustapha
M
Kassem
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Fei-Fei
FF
Liu
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.|Prince Naif Health Research Center, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Abdullah
A
Aldahmash
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Nehad M
NM
Alajez
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D055751:SOXC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; C107585:FOXM1 protein, human; C484579:FOXQ1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C572916:MIRN320 microRNA, human; D035683:MicroRNAs; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D005472:Fluorouracil
FOXM1; FOXQ1; SOX4; colorectal cancer; miR-320