Abstract
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.
Highlights
More and more evidence has showed that mRNAs possess the regulatory properties to modulate gene expression independent of its protein-coding function
Given that the functions of RNAs are closely associated with their secondary structures, we first predicted the secondary structures of 196 mRNA 3′-untranslated region (3′UTR) by using the software of RNAdraw[28] and RNAstructure[29]
Our data showed that the structures of mRNA 3′UTRs were complicated at different free energy levels, 10.7% (21/196) mRNA 3′UTRs displayed the hairpins that were relatively stable as compared with other hairpin structures (Supplementary Table S1)
Summary
More and more evidence has showed that mRNAs possess the regulatory properties to modulate gene expression independent of its protein-coding function. Our group has reported that a hairpin within the YAP (or PTEN) mRNA 3′-untranslated region (3′UTR) can serve as a regulatory element, which modulates the gene expression through generating a fragment[13, 14]. The elements such as hairpin based on the secondary structure of mRNAs play crucial roles in the gene regulation in the cells. Our finding provides new insights into the mechanism by which HMGA2 promotes hepatocarcinogenesis
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