Study On The Characteristics And Mechanism Of Liver Progenitor Cells Related Regeneration In Chronic Liver Diseases And Liver Carcinomas

Background & Aim: To compare the liver ductular reaction in chronic hepatitis B and schistomiasis related liver disease and the underlying mechanism.To explore the relationship between peritumoral ductular reation and the activation of β-catenin and the characteristics of peritumoral DR in CK19 positive and negative HCC.To explore the effect of peritumoral ductular reaction and CD133 expression on non-mucin-producing intrahepatic cholangiocarcinomor(ICC)and the mechanisms.Methods: The relationship between DR/LPC and liver inflammation and fibrosis in the diseases were also compared.The effects of different cytokines on the proliferation of LPC were evaluated by in vitro experiments.Liver specific Smad7 transgene mice were applied to analyze the change of liver DR after the inhibition of TGF-β signaling.120 HCC patients were included and the relationship between the expressions of CK19,β-catenin and peritumoral ductular reaction were analysized.Non-mucin-produing ICC patients were included.We analyzed the relationship between peritumor DR and clinicopathological parameters or prognosis.CD133 expression in ICC was evaluated by IHC staining.The difference of clinicopathological parameters and prognosis were compared between CD133 positive and negative ICC groups.Results: In chronic hepatitis B,liver ductular reation and LPC amount are positively related with liver inflammation and fibrosis.However,this relation was not significant in schistomiasis or hepatitis B combined with schistomiasis patients.In vitro experiments indicated that TNF-α could increase the proliferation of LPC while TGF-β inhibited the proliferation of LPC.When they were used to treat LPC together,their effects could be counteracted.Also,the liver specific Smad7 transgene mice with DDC diet model showed after DDC diet of 12 weeks,DR grade was significantly stronger than the wild type mice.Peritumoral ductular reation is positively related to local inflammation and fibrosis.The grade of peritumoral ductular reation is related to the nuclear expression of β-catenin in HCC.More tumor cells had PSmad2 expression in obvious peritumoral DR group than in mild peritumoral DR group.The malignant cells which had nuclear expression of β-catenin had more PSmad2 expression.The CK19 positive HCC had higher grade of peritumoral DR than the CK19 negative HCC.In ICC patients,the recurrence rate in the mild peritumoral DR group was lower than in the significant peritumoral DR group.The survival analysis demonstrated the overall survival and disease-free survival rate in the significant peritumoral DR group were lower than in the mild peritumoral DR group.Compared to the CD133 negative ICCs,the CD133 positive ICCs had higher metastasis rate at the time of diagnosis and higher recurrence rate after resection.The survival analysis also indicated that the overall survival and disease-free survival rate in the CD133 positive ICCs were lower than in the CD133 negative ICCs.The CD133 positive ICCs also had higher TGF-β and PSmad2 expression in the malignant cells.Conclusions: Our study demonstrated that patients with schistomiasis had low level of ductular reation in liver which is independent of liver inflammation and fibrosis and contrary to chronic hepatitis B.The expaination may be that lack of Th1 cytokines like TNF-α and TWEAK leads to the dominant inhibition effect on LPC by TGF-β.CK19 positive HCC patients had stronger peritumoral DR.Nuclear expression of β-catenin was higher in obvious peritumoral DR group than in mild peritumoral DR group and activation of TGF-β signaling may be the cause.The significant peritumoral DR ICC patients are easier to have a poor prognosis.However,the exact mechanism needs to be further investigated.CD133 posive ICC patient are easier to encounter metastasis and recurrence after resection.The possible reason may be that the autocrine TGF-β induce the epithelial mesenchymal transition of the tumor cells.