miR-424-3p promotes metastasis of hepatocellular carcinoma via targeting the SRF-STAT1/2 axis

Author:

Feng Lan1,Chen Xi1,Li Peiyao1,Li Yuanfeng1,Zhai Yun1,Liu Xinyi1,Jin Qian1,Zhang Hongxing2,Yu Chaohui3,Xing Baocai4,Cui Ying5,Cao Pengbo1,Zhou Gangqiao1678ORCID

Affiliation:

1. State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine , Beijing , China

2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Lifeomics , Beijing , China

3. Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou , China

4. Key Laboratory of Carcinogenesis and Translational Research, Department I of Hepatopancreatobiliary Surgery, Cancer Hospital and Institute, Peking University , Beijing , China

5. Affiliated Cancer Hospital of Guangxi Medical University , Nanning , China

6. Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University , Nanjing , China

7. Anhui Medical University , Hefei , China

8. Hebei University , Baoding , China

Abstract

Abstract Although emerging evidence has established the roles of miRNAs in hepatocellular carcinoma (HCC), the global functional implication of miRNAs in this malignancy remains largely uncharacterized. Here, we aim to systematically identify novel miRNAs involved in HCC and clarify the function and mechanism of specific novel candidate miRNA(s) in this malignancy. Through an integrative omics approach, we identified ten HCC-associated functional modules and a collection of candidate miRNAs. Among them, we demonstrated that miR-424-3p, exhibiting strong associations with extracellular matrix (ECM), promotes HCC cells migration and invasion in vitro and facilitates HCC metastasis in vivo. We further demonstrated that SRF is a direct functional target of miR-424-3p, and is required for the oncogenic activity of miR-424-3p. Finally, we found that miR-424-3p reduces the interferon pathway by attenuating the transactivation of SRF on STAT1/2 and IRF9 genes, which in turn enhances the matrix metalloproteinases (MMPs)-mediated ECM remodeling. This study provides comprehensive functional relevance of miRNAs in HCC by an integrative omics analysis, and further clarifies that miR-424-3p in ECM functional module plays an oncogenic role via reducing the SRF-STAT1/2 axis in this malignancy.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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