Interferon-MicroRNA Signaling Drives Liver Precancerous Lesion Formation And Hepatocarcinogenesis

Part Ⅰ Interferon-Micro RNA Signaling Drives Liver Precancerous Lesion Formation and HepatocarcinogenesisBackground and Purpose: Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumorigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated, and their physiological significance.Method: Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumor tissues. mi R-484-/- and Ifnar1-/- mice were employed to determine the critical role of the interferon-micro RNA pathway in precancerous lesions formation and tumorigenesis. Luciferase reporter assay, ELISA assay and chromatin immunoprecipitation assay were applied to explore the underlying mechanisms.Results: mi R-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in mi R-484-/- mice. Mechanistically, specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of mi R-484 and cell transformation. Convincingly, formation of precancerous lesions was significantly attenuated in Ifnar1-/- mice.Conclusion: These findings demonstrate a new pro-tumorigenic axis involving type I IFN-micro RNA signaling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumorigenesis.Part Ⅱ CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating m TORC2/Akt SignalingBackground and Purpose: CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression.Method: Tissue microarray analysis was used to explore CYP3A5 expression levels in clinical samples. Zymograph assay was applied to detect the activation of MMPs. Nude mice pulmonary metastatic model was applied to study the functions of CYP3A5 in vivo.Results: In our study, we found that CYP3A5 is downregulated in hepatocellular carcinomas where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring m TORC2 but not Rictor/m TOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of m TORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity.Conclusion: Our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker.