Data from Frequent Overexpression of <i>HMGA2</i> in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with <i>let-7a3/let-7b</i> miRNA

Abstract

<div>Abstract<p><b>Purpose:</b> Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the <i>SMARCB1</i> tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of <i>let-7a3/let-7b</i> microRNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of <i>let-7</i> miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.</p><p><b>Experimental Design:</b> Genomic aberrations, <i>let-7a3/let-7b</i> miRNA and <i>HMGA2</i> expression in AT/RT tissues were identified using quantitative PCR, reverse transcription PCR (RT-PCR), and immunohistochemistry. The impact of <i>let-7b</i> miRNA on <i>HMGA2</i> expression and the malignant potential of human rhabdoid tumor cell G401 (<i>SMARCB1</i><sup>−/−</sup>) were investigated by antisense inhibition and ectopic overexpression studies.</p><p><b>Results:</b> The copy number of <i>let-7a3/let-7b</i> miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between <i>let-7a3</i>/let-7b miRNA expression and <i>HMGA2</i> mRNA expression was observed in AT/RT tissues (<i>R</i> = −0.34; <i>P</i> < 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15 of 18) of AT/RT tissues. Restoration of <i>let-7</i> miRNA or knockdown of <i>HMGA2</i> expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.</p><p><b>Conclusion:</b> Reduction of <i>let-7a3/let-7b</i> miRNA may be one of mechanisms leading to overexpression of <i>HMGA2</i> in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of patients with AT/RT. <i>Clin Cancer Res; 20(5); 1179–89. ©2014 AACR</i>.</p></div>