MicroRNA let-7 suppresses the oncogene HMGA2, which is involved in various tumors, including mesenchymal tumors and lung cancers. In HeLa cells, HMGA2 mRNA is destabilized in the cytoplasm through the miRNA pathway. Inhibition of let-7 derepresses HMGA2, while ectopic expression of let-7 reduces HMGA2 and cell proliferation in lung cancer cells. The effect of let-7 on HMGA2 is mediated through multiple target sites in the 3'UTR of HMGA2. Overexpression of HMGA2 without the 3'UTR rescues the growth-suppressive effect of let-7 on lung cancer cells. These findings suggest that let-7 suppresses HMGA2 by targeting its 3'UTR, and that chromosomal translocations can eliminate the 3'UTR, allowing HMGA2 to escape let-7 repression. The study highlights the role of miRNAs in tumor suppression by repressing oncogenic targets. Let-7 is a tumor suppressor miRNA that is downregulated in lung cancers, correlating with HMGA2 overexpression. The results indicate that let-7 contributes to the destabilization of HMGA2 mRNA, and that HMGA2 overexpression in tumors may result from chromosomal translocations that remove the 3'UTR, allowing HMGA2 to escape let-7 repression. The study also shows that let-7 can rescue growth inhibition by HMGA2 overexpression, suggesting a causal relationship between let-7 and HMGA2 in lung cancer development. The findings provide a novel example of miRNA-mediated suppression of an oncogene and suggest that chromosomal translocations can activate oncogenes by removing their 3'UTR, which is normally repressed by let-7.MicroRNA let-7 suppresses the oncogene HMGA2, which is involved in various tumors, including mesenchymal tumors and lung cancers. In HeLa cells, HMGA2 mRNA is destabilized in the cytoplasm through the miRNA pathway. Inhibition of let-7 derepresses HMGA2, while ectopic expression of let-7 reduces HMGA2 and cell proliferation in lung cancer cells. The effect of let-7 on HMGA2 is mediated through multiple target sites in the 3'UTR of HMGA2. Overexpression of HMGA2 without the 3'UTR rescues the growth-suppressive effect of let-7 on lung cancer cells. These findings suggest that let-7 suppresses HMGA2 by targeting its 3'UTR, and that chromosomal translocations can eliminate the 3'UTR, allowing HMGA2 to escape let-7 repression. The study highlights the role of miRNAs in tumor suppression by repressing oncogenic targets. Let-7 is a tumor suppressor miRNA that is downregulated in lung cancers, correlating with HMGA2 overexpression. The results indicate that let-7 contributes to the destabilization of HMGA2 mRNA, and that HMGA2 overexpression in tumors may result from chromosomal translocations that remove the 3'UTR, allowing HMGA2 to escape let-7 repression. The study also shows that let-7 can rescue growth inhibition by HMGA2 overexpression, suggesting a causal relationship between let-7 and HMGA2 in lung cancer development. The findings provide a novel example of miRNA-mediated suppression of an oncogene and suggest that chromosomal translocations can activate oncogenes by removing their 3'UTR, which is normally repressed by let-7.