Abstract
Frequent KRAS mutations contribute to multiple cancers including ~40% of human colorectal cancers (CRCs). Systematic screening of 1255 microRNAs (miRNAs) identified miR-30a as a synthetic lethal in KRAS-mutant CRC cells. miR-30a was downregulated in CRCs and repressed by P65. miR-30a directly targeted malic enzyme 1 (ME1) and KRAS, and inhibited anchorage-independent growth and in vivo tumorigenesis by KRAS-mutant CRC cells. ME1 was significantly upregulated in KRAS-mutant CRCs. Eliminating ME1 by short hairpin RNA (shRNA) resulted in obviously decreased NADPH production, levels of triglyceride and fatty acid, and an inhibition of tumorigenicity of KRAS-mutant CRCs. miR-30a overexpression and ME1 suppression attenuated AOM/DSS-induced colorectal tumorigenesis. The critical roles of miR-30a and ME1 in the development of KRAS-mutant CRCs indicate therapy potentials for this subtype of cancer.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (81472549 and 31521091) and the 973 Program of China (2016YFC1302300 and 2014CB910600).
Author contributions
HS and CX performed all experiments. HS and KC performed bioinformatics and statistical analyses. YL helped to perform the experiments of administration of lentivirus and other animal experiments. JZ provided human CRC specimens and pathology identification. RD and XZ provided reagents. HS and YL designed the study and wrote the manuscript.
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Shen, H., Xing, C., Cui, K. et al. MicroRNA-30a attenuates mutant KRAS-driven colorectal tumorigenesis via direct suppression of ME1. Cell Death Differ 24, 1253–1262 (2017). https://doi.org/10.1038/cdd.2017.63
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DOI: https://doi.org/10.1038/cdd.2017.63
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