Transgenic SND1 Delays The Development Of CCl₄ Induced Hepatic Fibrosis But Promotes Liver Carcinogenesis

Objectives:Multifunctional protein SND1 takes part in various processes of liver disease,including liver metabolism,hepatocarcinogenesis,hepatoangiogenesis and the proliferation of hepatocellular carcinoma cell line,while its role in hepatic fibrosis has not been revealed yet.The major aim of this research was to discover the potential effect of SND1 on hepatic fibrosis and the related molecular mechanisms.Incidentally,we observed hepatocellular carcinoma formation induced by long-lasting CCl₄ administration on SND1 global transgenic C57 mice,so we try to discuss the manifold functions of SND1 in discriminatory hepatic cell fractions as well as different process of liver disease.Methods:First of all,the differential expression of SND1 among hepatic fibrosis,liver cancer and the normal control clinical specimens was analyzed using the Oncomine database.Following the cue of bioinformatic analysis,the hepatic fibrosis model was induced by CCl₄ injection intraperitoneally for 12 weeks.Multiple assays were applied to compare the degree of hepatic fibrosis between global transgenic mice?TG?and the wild type control?WT?.The primary HSCs were isolated by density gradient centrifugation method,the ability of proliferation,chemotaxis,contraction and ECM secretion were assessed subsequently.Fluorescent confocal microscopy was used to identify the location of Hippo signaling transcriptional coactivator YAP/TAZ,while the transcription was evaluated by qPCR.Liver cancer incidence was compared between WT/TG group after long lasting CCl₄ administration,cell component and SND1 expression level were tested in the cancer and carcinoma adjacent.The hepatic expression of SND1 has also been detected via different modeling period.Results:1.SND1 is positively associated with hepatic fibrosis but negatively associated with liver cancer according to the Oncomine database,2.Global SND1 over-expression transgenic mice?TG?showed less liver fibrotic area,collagen concentration,lower transaminase and HSC activation marker protein level than the WT control group after CCl₄ injection intraperitoneally,3.Primary HSC of TG mice got weaker proliferative and chemotactic ability,expressed lower cytokines,ECM proteins and?-SMA,had an slacker cellular surface under scanning electron microscopy,4.SND1 over-expression in primary HSC tend to make more YAP/TAZ stay in the cytoplasm,down regulate the expression of Hippo target genes,5.With the prolongation of CCl₄ administration,the overexpression of SND1 in the hepatocytes of TG group weakened gradually until there was no obvious difference from the WT control.The level of SND1 overexpression in the hepatic stellate cells was not affected by the CCl₄,6.Liver cancer could be induced on global SND1 over-expression transgenic mice?TG?after long-lasting CCl₄ administration,expression of SND1 elevated after tumorigenesis,Kupffer cell population increased in the hepatic cancer foci.Conclusion:1.SND1 may delay the development of hepatic fibrosis and activation of hepatic stellate cells,2.SND1 may induce the occurrence of hepatocellular carcinoma by altering the liver immune microenvironment,the expression of SND1 is increased in hepatocytes after hepatocarcinogenesis.