State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China.
State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, 300071, China.
Sci Rep. 2017 May 18;7(1):2070. doi: 10.1038/s41598-017-02311-0.
High mobility group A2 (HMGA2) plays a crucial role in the development of cancer. However, the mechanism by which HMGA2 promotes the growth of hepatocellular carcinoma (HCC) remains unclear. Here, we explore the hypothesis that HMGA2 may enhance the growth of hepatoma cells through a fragment based on the secondary structure of HMGA2 mRNA 3'-untranslated region (3'UTR). Bioinformatics analysis showed that HMGA2 mRNA displayed a hairpin structure within its 3'UTR, termed HMGA2-sh. Mechanistically, RNA immunoprecipitation assays showed that the microprocessor Drosha or DGCR8 interacted with HMGA2 mRNA in hepatoma cells. Then, Dicer contributes to the generation of the fragment HMGA2-sh-3p20 from the HMGA2-sh. HMGA2-sh-3p20 was screened by PCR analysis. Interestingly, HMGA2-sh-3p20 increased the expression of HMGA2 through antagonizing the tristetraprolin (TTP)-mediated degradation of HMGA2. HMGA2-sh-3p20 inhibited the expression of PTEN by targeting the 3'UTR of PTEN mRNA. In addition, the overexpression of PTEN could downregulate HMGA2 expression. Significantly, we documented the ability of HMGA2-sh-3p20 to promote the growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR promotes the growth of hepatoma cells by upregulating HMGA2. Our finding provides new insights into the mechanism by which HMGA2 enhances hepatocarcinogenesis.
高迁移率族蛋白 A2（HMGA2）在癌症的发展中起着至关重要的作用。然而，HMGA2 促进肝细胞癌（HCC）生长的机制尚不清楚。在这里，我们提出了一个假设，即 HMGA2 可能通过基于 HMGA2 mRNA 3'非翻译区（3'UTR）二级结构的片段来增强肝癌细胞的生长。生物信息学分析表明，HMGA2 mRNA 在其 3'UTR 内显示出发夹结构，称为 HMGA2-sh。从机制上讲，RNA 免疫沉淀测定表明 Drosha 或 DGCR8 与肝癌细胞中的 HMGA2 mRNA 相互作用。然后，Dicer 有助于从 HMGA2-sh 生成片段 HMGA2-sh-3p20。通过 PCR 分析筛选 HMGA2-sh-3p20。有趣的是，HMGA2-sh-3p20 通过拮抗三丝氨酸脯氨酸（TTP）介导的 HMGA2 降解来增加 HMGA2 的表达。HMGA2-sh-3p20 通过靶向 PTEN mRNA 的 3'UTR 来抑制 PTEN 的表达。此外，PTEN 的过表达可以下调 HMGA2 的表达。重要的是，我们记录了 HMGA2-sh-3p20 在体外和体内促进肝癌细胞生长的能力。因此，我们得出结论，HMGA2 mRNA 3'UTR 的片段 HMGA2-sh-3p20 通过上调 HMGA2 促进肝癌细胞的生长。我们的发现为 HMGA2 增强肝癌发生的机制提供了新的见解。
