miR-424-3p promotes metastasis of hepatocellular carcinoma via targeting the SRF-STAT1/2 axis
miR-424-3p promotes metastasis of hepatocellular carcinoma via targeting the SRF-STAT1/2 axis
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DOI：
10.1093/carcin/bgad037
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发表时间：
2023-05-26
期刊：
影响因子：
4.7
通讯作者：
Zhou，Gangqiao
中科院分区：
文献类型：
--
作者：
Feng，Lan;Chen，Xi;Zhou，Gangqiao
虽然新出现的证据已经确定了miRNAs在肝细胞癌（HCC）中的作用，但miRNAs在这种恶性肿瘤中的全球功能意义仍然很大程度上没有被表征。在此，我们的目标是系统地识别新的参与HCC的miRNA，并阐明特定的新的候选miRNA在这种恶性肿瘤中的功能和机制。通过整合组学的方法，我们确定了10个HCC相关的功能模块和候选miRNAs的集合。其中，我们发现miR-424- 3 p与细胞外基质（ECM）有很强的结合，在体外可促进肝癌细胞的迁移和侵袭，在体内可促进肝癌的转移。我们进一步证明了SRF是miR-424- 3 p的直接功能靶点，并且是miR-424- 3 p的致癌活性所必需的。最后，我们发现miR-424- 3 p通过减弱SRF对STAT 1/2和IRF 9基因的反式激活，从而减少干扰素通路，进而增强基质金属蛋白酶（MMPs）介导的ECM重塑。本研究通过整合组学分析提供了miRNA在HCC中的全面功能相关性，并进一步阐明了ECM功能模块中的miR-424- 3 p在该恶性肿瘤中发挥致癌作用，诱导SRF-STAT 1/2轴。
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 invasionin vitroand facilitates HCC metastasisin vivo. We further demonstrated thatSRFis 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 onSTAT1/2andIRF9genes, 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 roleviareducing the SRF-STAT1/2 axis in this malignancy.