Abstract
BackgroundMicroRNAs (miRNAs or miRs) are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that also become dysregulated in cancer development. In the latter context, studies to date have focused on high-abundance miRNAs and their targets. We hypothesized that among the pool of low-abundance miRNAs are some with the potential to impact crucial oncogenic signaling networks in colon cancer.ResultsUnbiased 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.ConclusionsEvolutionarily 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.
Highlights
MicroRNAs are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that become dysregulated in cancer development
Loss of the Krüppel-like factor 4 (KLF4) region on chromosome 9q is reported in 25% to 50% of sporadic colorectal cancers, and a significant decrease in KLF4 expression is observed in adenomas and adenocarcinomas of the large and small intestine [22,23]
Metacore pathway analysis predicted multiple targets of miR-206, including KLF4 (Figure 1A), which was further supported by sequence complementarity alignment (Figure 1B)
Summary
MicroRNAs (miRNAs or miRs) are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that become dysregulated in cancer development. In the latter context, studies to date have focused on high-abundance miRNAs and their targets. Lin et al [12] identified an autoregulatory feedback loop between miR-206 and Krüppel-like factor 4 (KLF4) This zinc finger protein plays a crucial role in early development and cancer stem-cell biology [13]. Loss of the KLF4 region on chromosome 9q is reported in 25% to 50% of sporadic colorectal cancers, and a significant decrease in KLF4 expression is observed in adenomas and adenocarcinomas of the large and small intestine [22,23]
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