Hepatitis B virus (HBV)-induced liver necrosis takes great part in liver cirrhosis progression. However, less is known about whether hepatitis B virus X protein (HBx) has effect on liver fibrosis. Here, we report that HBV leads to liver fibrosis and hepatocarcinogenesis through miR-30e targeting P4HA2. HBV transgenic mouse was treated by CCl to generate a model of liver fibrosis. A crucial enzyme catalyzing collagen formation, prolyl 4-hydroxylase subunit α2 (P4HA2) was evaluated by immunohistochemistry, western blotting or quantitative reverse transcription-PCR analysis. The function of HBV-modulated P4HA2 in hepatoma cell growth in vitro and in vivo was analyzed by EdU, MTT, colony-forming assay and animal transplantation assay. HBV transgenic mice exhibited more collagen deposition in liver after intraperitoneal injection of CCl. P4HA2 was dramatically augmented in liver samples of HBV transgenic mice, clinical liver cirrhosis and liver cancer patients. Mechanistically, HBx was capable of inducing P4HA2 through suppressing miR-30e, in which miR-30e could target P4HA2 mRNA 3' untranslated region in liver cancer cells. HBx inhibited the miR-30e expression through increasing methylation of CpG islands in its promoter mediated by EZH2-formed complexes. Functionally, HBx-elevated P4HA2 enhanced the collagen deposition in the liver in vivo and in vitro, leading to liver fibrosis and liver cancer progression. In conclusion, HBx promotes the development of liver fibrosis and hepatocellular carcinoma through miR-30e targeting P4HA2 mRNA. We provide novel perspective on how HBx induces liver fibrosis.
Rapid genomic change has been demonstrated in several allopolyploid plant systems; however, few studies focused on animals. We addressed this issue using an allotetraploid lineage (4nAT) of freshwater fish originally derived from the interspecific hybridization of red crucian carp (Carassius auratus red var., ♀, 2n=100) × common carp (Cyprinus carpio L., ♂, 2n=100). We constructed a bacterial artificial chromosome (BAC) library from allotetraploid hybrids in the 20th generation (F20) and sequenced 14 BAC clones representing a total of 592.126 kb, identified 11 functional genes and estimated the guanine–cytosine content (37.10%) and the proportion of repetitive elements (17.46%). The analysis of intron evolution using nine orthologous genes across a number of selected fish species detected a gain of 39 introns and a loss of 30 introns in the 4nAT lineage. A comparative study based on seven functional genes among 4nAT, diploid F1 hybrids (2nF1) (first generation of hybrids) and their original parents revealed that both hybrid types (2nF1 and 4nAT) not only inherited genomic DNA from their parents, but also demonstrated rapid genomic DNA changes (homoeologous recombination, parental DNA fragments loss and formation of novel genes). However, 4nAT presented more genomic variations compared with their parents than 2nF1. Interestingly, novel gene fragments were found for the iqca1 gene in both hybrid types. This study provided a preliminary genomic characterization of allotetraploid F20 hybrids and revealed evolutionary and functional genomic significance of allopolyploid animals.
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