Roles Of MicroRNAs In Viral Infection And Hepatocellular Carcinoma

Upon recognition of viral components by pattern-recognition receptors, including Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs), cells are activated to produce type I interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can downregulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNAs) to date. We found that vesicular stomatitis virus (VSV) infection upregulated miR-146a expression in mouse macrophages. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), we proved that IRAK2 was another target of miR-146a, which also participated in RIG-I signaling. Furthermore, IRAK1 and IRAK2 participated in RIG-I signaling by associating with Fas-associated death domain-containing protein (FADD), an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, upregulated during viral infection, is a negative regulator of RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1 and IRAK2.The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be identified. Here we applied Illumina massively parallel high throughput sequencing to carry out an in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC). We found that expressions of 9 miRNAs account for ~88.2% of the miRNome in human normal liver. miR-199a/b-3p, the third most enriched miRNA in normal liver, is markedly and consistently decreased in HCC, and its decrement, due to deregulated histone methylation, significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting p21-activated protein kinase 4 (PAK4) to suppress HCC growth through inhibiting PAK4/mitogen activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK (PAK4/Raf/ MEK/ERK) pathway both in vitro and in vivo. Therefore, miRNomes of human normal liver and HCC are firstly provided, contributing to a better understanding of the most important deregulated miRNA in pathogenesis of HCC and suggesting a potential therapeutic target for HCC therapy.