However, we presented the further evidence that expression of other proteins of HBV have no significant effect on miR-122. Taken together, the results from our study and those of others support that HBV and HBx down-regulate miR-122 levels in hepatic cells. However, the route that HBV takes to reduce miR-122 levels remains controversial. MicroRNA levels are related to transcription, processing, and turnover. Two recent studies have provided two different explanations for the mechanism of miR-122 down-regulation. Meng et al. found that transfection of pHBV1.3 in Huh7 cells could increase that HBV did not down-regulate miR-122 levels via the transcription pathway. Although the results of Tong et al. indicated that HBx protein could reduce miR-122 promoter activity by binding to PPARc in both HepG2 and Huh7 cells, we found that the activities of the miR-122 promoter varied in different cell lines expressing HBx proteins. Despite these findings, pre-miR-122 in all of the three cells lines did not decrease when HBV or HBx was expressed. The selected promoter sequences of miR-122 were essentially the same as those of the previous two related studies. However, the different results might be due to the different experimental conditions and/ or different cell lines. In previous studies, HBx was found to inhibit the normal function of p53 and p53 could inhibit the expression of hepatocyte nuclear factor 4a, a key regulator of miR-122 expression in the liver. It may implicate that HBx could potentially affect miR-122 promoter activity indirectly and these effects could change under different conditions and/or different cell lines. In the cell lines we used, HepG2 cells were found to express small amounts of wild type p53, whereas Huh7 cells were shown to express mutation p53. What’s more, HNF4a was up-regulated in HBV-infected cells. Though further evidence is needed, it may explain the increased miR-122 promoter activities in QSG7701 and HepG2 cells but not in Huh7 cells. Moreover, we also had the hypothesis that there might be some Vorinostat HDAC inhibitor feedback signal to stimulate the miR-122 promoter when the miR-122 was reduced by HBx, for the positive or negative feedback control signal is often exist to maintain the normal levels of a special object in cells. In addition, HBx was found to down-regulate the Drosha which participate in processing pri-miRNA to release pre-miRNA. It may explain the increased miR-122 promoter activities resulted in the similar premiR-122 levels. Thus, the relationship between HBx and miR-122 may be more complicated than we have known. Since the transcription pathway cannot always explain the low miR-122 levels in HBx-expressing cells, there must be other pathway related to the down-regulation of miR-122 induced by HBx. Gld2 has been shown to have important effects on the stability of many miRNAs, including miR-122, via catalysed 39 monoadenylation. A decrease in Gld2 levels could cause a reduction in mature miR-122 levels but not pre-miR-122 levels.