Mir-483-5p介导的IGF2/H19增强子激活通过染色质环上调IGF2/H19表达，从而促进肝细胞癌的恶性进展。

Mir-483-5p-mediated activating of IGF2/H19 enhancer up-regulates IGF2/H19 expression via chromatin loops to promote the malignant progression of hepatocellular carcinoma.

作者信息

Chen Weiwei, Wu Chutian, Li Yuting, Wang Tonghua, Huang Miaoling, Wang Min, Long Linjing, Chen Yanfang, Feng Shufen, Liu Xuyou, Tang Shaohui

机构信息

Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510630, P. R. China.

Department of Gastroenterology, The First People's Hospital of Zunyi, (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, P. R. China.

出版信息

Mol Cancer. 2025 Jan 11;24(1):10. doi: 10.1186/s12943-024-02204-7.

DOI:10.1186/s12943-024-02204-7

PMID:39799319

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11724483/

Abstract

BACKGROUND

The insulin-like growth factor 2 (IGF2) and H19 are overexpressed in hepatocellular carcinoma (HCC). IGF2-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in IGF2 and H19 overexpression regulation and its role in HCC.

METHODS

Firstly, the effect of miR-483-5p on the expression of IGF2 and H19, and the binding of miR-483-5p to IGF2/H19 enhancer were evaluated in HCC cells. Next, miR-483-5p-mediated IGF2/H19 enhancer activation and its mechanism were investigated in HCC cells. Then, the mechanism by which active IGF2/H19 enhancer mediated by miR-483-5p activate IGF2/H19 promoters was studied in HCC cells. Finally, the effect of MED1 on the expression of IGF2/H19 as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p was evaluated.

RESULTS

Mir-483-5p up-regulated IGF2 P2 mRNA-P4 mRNA and H19 expression by binding to IGF2/H19 enhancer resulting in IGF2/H19 enhancer activation in HCC cells. Mechanistically, miR-483-5p increased recruitment of Ago1 and Ago2 at IGF2/H19 enhancer and then activated transcription of IGF2/H19 eRNA by RNA polymerase II and p300, which further induced chromatin loops formation between IGF2/H19 enhancer and IGF2/H19 promoters to activate IGF2/H19 promoters via IGF2/H19 eRNA-MED1-IGF2/H19 promoters complex in HCC cells. In this process, MED1 promoted chromatin loops formation as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p.

CONCLUSIONS

miR-483-5p-mediated activating of IGF2/H19 enhancer up-regulates IGF2/H19 expression via DNA loops, thereby promoting the malignant progression of HCC.

摘要

背景

胰岛素样生长因子2（IGF2）和H19在肝细胞癌（HCC）中过表达。IGF2衍生的miR-483-5p与癌症的发生发展有关。在此，我们研究了miR-483-5p在IGF2和H19过表达调控中的作用及其在HCC中的作用。

方法

首先，在HCC细胞中评估miR-483-5p对IGF2和H19表达的影响，以及miR-483-5p与IGF2/H19增强子的结合。接下来，在HCC细胞中研究miR-483-5p介导的IGF2/H19增强子激活及其机制。然后，在HCC细胞中研究miR-483-5p介导的活性IGF2/H19增强子激活IGF2/H19启动子的机制。最后，评估MED1对IGF2/H19表达的影响以及miR-483-5p在体外和体内介导的HCC细胞恶性表型的影响。

结果

Mir-483-5p通过与IGF2/H19增强子结合上调IGF2 P2 mRNA-P4 mRNA和H19表达，导致HCC细胞中IGF2/H19增强子激活。机制上，miR-483-5p增加了Ago1和Ago2在IGF2/H19增强子处的募集，然后通过RNA聚合酶II和p300激活IGF2/H19 eRNA的转录，这进一步诱导了IGF2/H19增强子与IGF2/H19启动子之间的染色质环形成，从而通过IGF2/H19 eRNA-MED1-IGF2/H19启动子复合物在HCC细胞中激活IGF2/H19启动子。在此过程中，MED1促进了染色质环的形成以及miR-483-5p在体外和体内介导的HCC细胞的恶性表型。