It is important to note that upon RIG I
It is important to note that upon RIG-I activation, IRF-3, p38, and ERK were activated by 3p-siHBx, leading to upregulated IFN response (Fig. 6). This suggests that 3p-siHBx has specific effects on HBV replication. In addition, 3p-siHBx induced type III IFN response (Fig. 6D), which could also inhibit HBV replication. We speculate that the type III IFN response might be partially attributed to anti-viral effect mediated by 3p-siHBx. In relation to the evaluation of the experiments shown in Fig. 6F, silencing RIG-I partially recovered HBV inhibition. Therefore, we presume that the effect of 3p-siHBx might not only 94 7 on its RNAi activity but also on RIG-I activating activity. In addition to RIG-I, previous studies have indicated that Toll-like receptor (TLR)7/8/9 or STING (transmembrane protein 173) agonists can activate the intrahepatic innate immune responses, which can control HBV infection efficiently. Therapeutic strategies based on pathogen recognition receptor (PRR) activation are intended to activate the antiviral signaling pathway that suppresses HBV replication and simultaneously reverse HBV-specific T cell exhaustion (Thursz, 2014; Urcuqui-Inchima et al., 2017). A potent and orally available TLR7 agonist (GS-9620) activated B cells, CD8+ T cells, and/or NK cells and induced type I/II IFN response in the liver microenvironment (Menne et al., 2015). Moreover, ssRNA40, a TLR8 agonist, selectively activated NKT and CD56bright NK cells to produce IFN-γ in HBV-infected livers (Jo et al., 2014).
Interestingly, 3p-siHBx could recruit NK cells and T cells (Fig. 7); it is possible that DC mutation in PBMCs and chemokine secretion of 3p-siHBx treated HBV + hepatocytes contributed to this process. Therefore, RIG-I is likely to play dual roles as an innate sensor and as a direct antiviral effector for host defense during viral infection. Whether TLR 7/8/9 or STING activation promotes the recruitment of NK and T cells in HBV models need to be further studied.
RNAi has been widely used to interference HBV infection in basic research. As the smallest open reading frame and also the most obvious overlap on the structure of the HBV genome region, HBx is required for HBV efficient replication, thus making it a potentially useful target for antiviral therapy (Belloni et al., 2009). Nowadays, the most effective and clinically advanced siRNA delivery systems should be investigated to protect siRNA from degradation in vivo. And a clinical trial of ARC-520 based on RNAi surpassed expectations (Liu et al., 2016). Our study might provide a candidate strategy for the development of a nucleic acid drug for therapy of not only virus infections, including HBV, but also for different tumors. 3p-siHBx is expected to be a promising immunomodulatory drug for improving treatment efficacy by abrogating immunosuppression.
Ethics approval and consent to participate
Fundings This work was supported by Shandong Provincial Key Research and Development Program [grant number 2017GSF18159], Shandong Provincial Natural Science Foundation, China [grant number ZR2017BH029, BS2015YY023], Fundamental Research Fund of Shandong University (2017JC004), and the National Natural Science Foundation of China (grant number 81601441).
Introduction Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) can participate in diverse physiological and pathological processes and affect disparate cellular functions [, , , ]. LncRNAs are transcripts longer than 200 bp that do not have any apparent protein-coding ability [5,6]. The first lncRNA found to be specifically overexpressed in hepatocellular carcinoma (HCC) is known as highly up-regulated in liver cancer (HULC) . HULC is thought to act as an endogenous sponge, because it down-regulates a series of microRNA activities, including those of miR-372 and miR-107 [8,9]. Moreover, our lab previously reported that HULC modulated abnormal lipid metabolism in hepatoma cells through a miR-9–mediated RXRA signaling pathway . However, the role of HULC in hepatocarcinogenesis is poorly understood.