Peng Yi, Laser Jordan, Shi Guizhi, Mittal Khush, Melamed Jonathan, Lee Peng, Wei Jian-Jun
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Mol Cancer Res. 2008 Apr;6(4):663-73. doi: 10.1158/1541-7786.MCR-07-0370.
High-mobility group A2 (HMGA2) is commonly overexpressed in large leiomyomas. HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation. As a predicted target of Let-7 microRNAs (Let-7s), HMGA2 can be repressed by Let-7s in vitro. MicroRNA profiling analysis revealed that Let-7s were significantly dysregulated in uterine leiomyomas: high in small leiomyomas and lower in large leiomyomas. To evaluate whether Let-7 repression of HMGA2 plays a major role in leiomyomas, we analyzed the molecular relationship of HMGA2 and Let-7s, both in vitro and in vivo. We first characterized that exogenous Let-7 microRNAs could directly repress the dominant transcript of HMGA2, HMGA2a. This repression was also identified for two cryptic HMGA2 transcripts in primary leiomyoma cultures. Second, we found that the endogenous Let-7s were biologically active and played a major role in the regulation of HMGA2. Then, we illustrated that Let-7 repression of HMGA2 inhibited cellular proliferation. Finally, we examined the expression levels of Let-7c and HMGA2 in a large cohort of leiomyomas (n = 120), and we found high levels of Let-7 and low levels of HMGA2 in small leiomyomas, and low levels of Let-7 and high levels of HMGA2 in large leiomyomas. Our findings suggest that the Let-7-mediated repression of HMGA2 mechanism can be an important molecular event in leiomyoma growth.
高迁移率族蛋白A2（HMGA2）在大的平滑肌瘤中通常过度表达。HMGA2是细胞生长、分化、凋亡和转化的重要调节因子。作为Let-7微小RNA（Let-7s）的预测靶点，HMGA2在体外可被Let-7s抑制。微小RNA谱分析显示，Let-7s在子宫平滑肌瘤中显著失调：在小的平滑肌瘤中水平较高，而在大的平滑肌瘤中水平较低。为了评估Let-7对HMGA2的抑制在平滑肌瘤中是否起主要作用，我们在体外和体内分析了HMGA2与Let-7s之间的分子关系。我们首先确定外源性Let-7微小RNA可直接抑制HMGA2的主要转录本HMGA2a。在原发性平滑肌瘤培养物中的两种隐秘HMGA2转录本中也发现了这种抑制作用。其次，我们发现内源性Let-7s具有生物学活性，在HMGA2的调节中起主要作用。然后，我们证明Let-7对HMGA2的抑制作用可抑制细胞增殖。最后，我们检测了一大组平滑肌瘤（n = 120）中Let-7c和HMGA2的表达水平，发现小的平滑肌瘤中Let-7水平高而HMGA2水平低，大的平滑肌瘤中Let-7水平低而HMGA2水平高。我们的研究结果表明，Let-7介导的对HMGA2的抑制机制可能是平滑肌瘤生长中的一个重要分子事件。
