A role for low-abundance miRNAs in colon cancer: the miR-206/Krüppel-like factor 4 (KLF4) axis

Unbiased screening of over 650 miRNAs identified miR-206, a low-abundance miRNA, as the most significantly altered miRNA in carcinogen-induced rat colon tumors. Computational modeling highlighted the stem-cell marker Krüppel-like factor 4 (KLF4) as a potential target of miR-206. In a panel of primary human colon cancers, target validation at the mRNA and protein level confirmed a significant inverse relationship between miR-206 and KLF4, which was further supported by miR-206 knockdown and ectopic upregulation in human colon cancer cells. Forced expression of miR-206 resulted in significantly increased cell proliferation kinetics, as revealed by real-time monitoring using HCT116 cells.Evolutionarily conserved high-abundance miRNAs are becoming established as key players in the etiology of human cancers. However, low-abundance miRNAs, such as miR-206, are often among the most significantly upregulated miRNAs relative to their expression in normal non-transformed tissues. Low-abundance miRNAs are worthy of further investigation, because their targets include KLF4 and other pluripotency and cancer stem-cell factors.MicroRNAs (miRNAs or miRs) influence multiple stages of cancer development, via post-transcriptional mechanisms that degrade or repress target messenger RNAs (mRNAs) [1]. Several miRNAs with critical roles in early embryonic development [2] become aberrantly expressed in tumors [3]. For example, miR-21 is a high-abundance miRNA upregulated in cancers of the breast, lung, colon, liver, pancreas, prostate, esophagus, brain, and thyroid; targets of miR-21 include phosphatase and tensin homolog, tropomyosin 1, and programmed cell death 4 [4,5].Evolutionarily conserved high-abundance miRNAs, such as miR-21, have been profiled in various human cancers [6-8], but little is known about the role of low-abundance miRNAs. We hypothesized that certain low-abundance miRNAs might regulate key players in normal physiology such that, under normal circumstances, their expres