Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma

Author:

Tao Liye,Wang Yali,Shen Zefeng,Cai Jingwei,Zheng Junhao,Xia Shunjie,Lin Zhongjie,Wan Zhe,Qi Haiou,Jin Renan,Wang Ling,Xu Junjie,Liang XiaoORCID

Abstract

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy. Although its incidence is lower than that of hepatocellular carcinoma (HCC), ICC has a worse prognosis, and it is more prone to recur and metastasize, resulting in a far greater level of malignancy. Methods Bioinformatics analysis and qRT-PCR were applied to assess the level of miR-122-5p and IGFBP4. Western blot, transwell assays, wound-healing assays, real-time cellular invasion monitoring, in vivo study were applied to explore the function of miR-122-5p and IGFBP4. Dual luciferase reporter assays and chromatin isolation by RNA purification (ChiRP) were applied to explore the regulation of IGFBP4 by miR-122-5p. Results Using The Cancer Genome Atlas (TCGA) data set, Sir Run Run Shaw hospital data set and bioinformatics analyses, we identified miR-122-5p as a potential tumor suppressor in ICC and validated its suppressive effect in metastasis and invasion of ICC. Transcriptome sequencing, rescue and complement experiments were used to identify insulin-like growth factor binding protein 4 (IGFBP4) as a target of miR-122-5p. The mechanism by which miR-122-5p regulates IGFBP4 was clarified by chromatin separation RNA purification technology, and dual-luciferase reporter assays. We discovered a rare novel mechanism by which miR-122-5p promotes IGFBP4 mRNA transcription by binding to its promoter region. Furthermore, in mouse orthotopic metastasis model, miR-122-5p inhibited the invasion of ICC. Conclusion In summary, our study revealed a novel mechanism of miR-122-5p and function of the miR-122-5p/IGFBP4 axis in the metastasis of ICC. We also highlighted the clinical value of miR-122-5p and IGFBP4 in inhibiting ICC invasion and metastasis.

Funder

Key Research and Development Project of Zhejiang Province

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Zhejiang Major Medical Science and Technology Plan supported by National Health Commission of China

Health innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan

Fundamental Research Funds for the Central Universities

Medicine and Health Technology project from the Zhejiang Health Commission

Publisher

Springer Science and Business Media LLC

Subject

Hepatology

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