miR-548c-3p targets TRIM22 to attenuate the Peg–IFN–α therapeutic efficacy in HBeAg-positive patients with chronic hepatitis B

Chronic hepatitis B (CHB) patients treated with interferon shows encouraging results. However, its clinical efficacy is limited by significant individual differences in treatment responses. We identified an interferon-inducible effector, TRIM22, as the likely causal target of such differential responses. We found that TRIM22 was highly expressed in interferon-responsive patients and negatively correlated with HBV DNA and HBeAg serum levels. Stable cells overexpressing TRIM22 carried significantly less HBsAg, HBeAg, and HBV DNA, and cells with knocked-down TRIM22 by shRNA displayed higher levels of these markers than controls. Integrated bioinformatics analysis and subsequent experiments revealed that TRIM22 overexpression significantly increased the supernatant levels of IL-1β and IL-8, two important cytokines of NOD2/NF-κB pathway involved in interferon-induced antiviral activities. We identified three candidate microRNAs binding to 3′UTR of TRIM22 at various locations through typical imperfect paring using the TargetScan program. MiR-548c-3p appeared to be highly expressed, while the TRIM22 level was low in the suboptimal response group of CHB patients. The Luciferase reporter assay revealed an interaction between miR-548c-3p and the 3′UTR of TRIM22, leading to a controlled suppression of TRIM22 endogenous expression. This resulted in interferon's substantially weakened therapeutic efficacy, as indicated by the elevation of the serum levels of HBsAg, HBeAg and HBV DNA in miR-548c-3p-transfected HepAD38 cells. Our study demonstrated that a particular miR-548c-3p is the key negative regulator of TRIM22 in CHB patients with a weak response to interferon treatment, providing a novel marker and target in interferon-α therapy evaluation. •TRIM22 as a possible causal target of the differential IFN-α response.•TRIM22 overexpression significantly increased the levels of IL-1β and IL-8.•Low abundance of miR-548c could serve as a key inducer of high TRIM22 expression.•TRIM22 promises to be a novel marker of therapeutic response to IFN-α.•miR-548c-3p may be a potential regulatory target in IFN-α therapy.