The study investigates the role of the tumor suppressor microRNA let-7 in repressing the oncogene HMGA2. HMGA2, a high-mobility group protein, is overexpressed in various tumors, including lung cancers and benign mesenchymal tumors. The research shows that HMGA2 mRNA is destabilized in the cytoplasm through a microRNA-dependent pathway, and its expression is negatively regulated by let-7. Inhibition of let-7 in cells with high levels of the miRNA derepresses HMGA2, leading to increased cell proliferation. The effect of let-7 on HMGA2 is mediated through multiple target sites in the 3' untranslated region (UTR) of HMGA2. Overexpression of the HMGA2 ORF without the 3' UTR rescues the growth-suppressive effect of let-7 on lung cancer cells. The findings suggest that chromosomal translocations that activate HMGA2 oncogene by deleting the 3' UTR with let-7 target sites may be a mechanism for tumor development.The study investigates the role of the tumor suppressor microRNA let-7 in repressing the oncogene HMGA2. HMGA2, a high-mobility group protein, is overexpressed in various tumors, including lung cancers and benign mesenchymal tumors. The research shows that HMGA2 mRNA is destabilized in the cytoplasm through a microRNA-dependent pathway, and its expression is negatively regulated by let-7. Inhibition of let-7 in cells with high levels of the miRNA derepresses HMGA2, leading to increased cell proliferation. The effect of let-7 on HMGA2 is mediated through multiple target sites in the 3' untranslated region (UTR) of HMGA2. Overexpression of the HMGA2 ORF without the 3' UTR rescues the growth-suppressive effect of let-7 on lung cancer cells. The findings suggest that chromosomal translocations that activate HMGA2 oncogene by deleting the 3' UTR with let-7 target sites may be a mechanism for tumor development.