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.

中文翻译：

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miR-424-3p 通过靶向 SRF-STAT1/2 轴促进肝细胞癌的转移。

尽管新出现的证据已经确定了 miRNA 在肝细胞癌 (HCC) 中的作用，但 miRNA 在这种恶性肿瘤中的整体功能意义在很大程度上仍然未知。在这里，我们的目标是系统地鉴定与 HCC 相关的新 miRNA，并阐明特定的新候选 miRNA 在这种恶性肿瘤中的功能和机制。通过综合组学方法，我们鉴定了 10 个与 HCC 相关的功能模块和一系列候选 miRNA。其中，我们证明miR-424-3p与细胞外基质（ECM）有很强的相关性，在体外促进HCC细胞迁移和侵袭，并在体内促进HCC转移。我们进一步证明SRF是miR-424-3p的直接功能靶标，并且是miR-424-3p的致癌活性所必需的。最后，我们发现miR-424-3p通过减弱STAT1/2和IRF9基因上SRF的反式激活来减少干扰素通路，从而增强基质金属蛋白酶（MMP）介导的ECM重塑。本研究通过综合组学分析提供了 HCC 中 miRNA 的综合功能相关性，并进一步阐明 ECM 功能模块中的 miR-424-3p 通过减少该恶性肿瘤中的 SRF-STAT1/2 轴而发挥致癌作用。