The small non-coding RNA let-7 can act as a tumor suppressor, according to a new study appearing in Science. Mayr, Hemann and Bartel show that let-7 RNA negatively regulates the chromatin modulator Hmga2 and that disruption of this regulation enhances tumorigenesis.
Hmga2 is increased in a wide range of human tumors including pituitary adenomas and lipomas. The boost of Hmga2 production is often triggered by chromosome breakage and rejoining that shortens the distal end of the Hmga2 gene. The lost region of the Hmga2 gene codes for RNA sequences that are complementary to the let-7 microRNA. MicroRNAs (miRNAs) such as let-7 do not yield information for making a protein but instead they regulate other genes by pairing with their mRNA. Mayr and colleagues hypothesized that let-7 binding controls Hmga2 protein levels.
In support of their hypothesis, the authors found that changing the let-7 recognition sites in the Hmga2 mRNA relaxes the repression by let-7, leading to more Hgma2 protein, while supplying additional let-7 to cells reduces Hmga2 protein. They went on to address the potential role for this mechanism in human cancers. Disabling let-7 downregulation of Hmga2 in a human cell line made these cells more able to form tumors as compared to cells containing Hmga2 that is properly dialed down by let-7. Overall, this illustrates a likely tumor-inhibiting function for the non-coding RNA let-7 in limiting Hmga2 levels.
This study complements previous analyses of the consequences of Hmga2 misregulation for cancer development and convincingly demonstrates that disruption of a specific miRNA-mRNA interaction contributes to tumor formation.
This report appears online in advance of print on February 22, 2007 in Science.
David P. Bartel
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