Abstract
MicroRNAs play important roles in animal development, cell differentiation, and metabolism and have been implicated in human cancer. The let-7 microRNA controls the timing of cell cycle exit and terminal differentiation in Caenorhabditis elegans and is poorly expressed or deleted in human lung tumors. Here, we show that let-7 is highly expressed in normal lung tissue, and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells. Overexpression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division, providing evidence that let-7 functions as a tumor suppressor in lung cells. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes, and our work now shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7. This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways.
Highlights
Hundreds of microRNAs are encoded in animal genomes, where they provide important regulatory functions in development, apoptosis, life span, and metabolism [1, 2]
In contrast to robust let-7 expression in normal human lung tissue [14], let-7 is poorly expressed in lung tumors and lung cancer cell lines (Supplementary Fig. S3; refs. 4, 5)
We have shown that let-7 overexpression causes human cancer cells to decrease cell cycle progression (Figs. 2 and 3)
Summary
Hundreds of microRNAs (miRNA) are encoded in animal genomes, where they provide important regulatory functions in development, apoptosis, life span, and metabolism [1, 2]. A number of miRNAs have been linked to human cancer [3,4,5,6,7,8]: we refer to this class of miRNAs as ‘‘oncomirs’’ [9]. These are roughly divided into two groups, those miRNAs that are up-regulated or amplified in cancer and are likely to be acting as oncogenes, and those miRNAs deleted or down-regulated in cancer that are likely to be acting as tumor suppressors. In Caenorhabditis elegans, let-7 is temporally regulated and controls the timing of terminal differentiation, acting as a master temporal regulator of multiple genes required for cell cycle exit in
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