Abstract
BackgroundChronic liver fibrosis is an inevitable stage for the development of patients with chronic hepatitis B (CHB). However, anti-fibrotic therapies have been unsuccessful so far. The biological functions and molecular mechanisms of long non-coding RNAs (lncRNAs) in the host immune system during chronic hepatitis B virus (HBV) infection, especially in fibrosis, are still largely unknown.MethodThe total RNA of peripheral blood mononuclear cells (PBMCs) from asymptomatic carriers (ASCs) or CHB receiving at least 8 years of anti-viral treatments was analyzed using Arraystar microarray and validated via quantitative real-time PCR (qRT-PCR). Correlation analysis was conducted based on correlation coefficients, Clusterprofile, and RNA Interactome Database (RAID). The functions of lncRNA in monocytes were determined via loss-of-function RNAi or gain-of-function lentivirus assays. The expression levels of mRNAs or proteins were evaluated using qRT-PCR, western blotting assay, or enzyme linked immunosorbent assays (ELISA).ResultsA total of 1,042 mRNA transcripts (630 up-regulated and 412 down-regulated) were identified being differentially expressed between ASC and CHB patients. Through enrichment analysis we focused on the transforming growth factor beta (TGF-β) signaling pathway and validated their expression in a larger cohort. Moreover, we found that lncRNA ENST00000519726 (lncRNA-HEIM) was highly expressed in monocytes and further up-regulated upon HBV infection. LncRNA-HEIM played an important role in CHB patients with long-term antiviral treatments, and its elevated expression was remarkably correlated with the TGF-β signaling pathway, especially with the two members namely TGF-β and SMAD4. Furthermore, altering the endogenous lncRNA-HEIM level in monocytes significantly affected the production of TGF-β, as well as the fibrosis of hepatic stellate cells by affecting the expression of collagen I and α-smooth muscle actin (α-SMA).ConclusionThese findings not only added knowledge to the understanding of the roles of which lncRNA-HEIM played in the activation of HSCs in CHB patients with long-term medication, but also provided a promising therapeutic target in the future treatment for liver fibrosis.
Highlights
Viral hepatitis was the seventh leading cause of mortality worldwide and responsible for 1.4 million deaths per year [1]
Comparing with the asymptomatic carrier (ASC), we identified a total of 1,042 messenger RNAs (mRNAs) transcripts (630 up-regulated and 412 down-regulated, respectively) differently expressed in chronic hepatitis B (CHB) patients (Figure 1A)
Resorting to Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we focused on the up-regulated mRNAs and found that TGF-b was the only related signaling pathway among the top ten most enriched ones (Figure 1B)
Summary
Viral hepatitis was the seventh leading cause of mortality worldwide and responsible for 1.4 million deaths per year [1]. Chronic infections of hepatitis B virus (HBV) can lead to immune mediated liver damage which could further progress to cirrhosis and hepatocellular carcinoma (HCC) and is still incurable because of the persistence of a covalently closed circular DNA (cccDNA) of HBV in hepatocytes during the infection [2]. As a common outcome of chronic HBV infection, the patients with progressive liver fibrosis are at risk of developing into cirrhosis and liver cancer, and blocking the process of liver fibrosis becomes the key in treating chronic HBV infections [3]. Non-invasive methods which are accurate and reliable for the diagnosis of early liver fibrosis are urgently needed for the treatment of CHB patients, as well as therapies that could effectively block the progression of fibrosis. The biological functions and molecular mechanisms of long non-coding RNAs (lncRNAs) in the host immune system during chronic hepatitis B virus (HBV) infection, especially in fibrosis, are still largely unknown
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