Alpha 1 Antitrypsin in Pathogenesis of Hepatocellular Carcinoma

Abstract

ContextAlpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed.Evidence AcquisitionsSearch for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords “alpha-1-antitrypsin”, “liver diseases”, “hepatocellular carcinoma”, “SERPINA1”. Articles published until 2011 were reviewed.ResultsEpidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC.ConclusionsClarification of a carcinogenic role for A1ATD and identification of proinflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs.

Association between inherited monogenic liver disorders and chronic hepatitis C

“…Again, this may have been due to the small number of patients in our study and/or the fact that liver symptoms in patients with alpha-1 antitrypsin deficiency more commonly manifest in childhood or late adulthood. Advanced liver disease generally occurs around the age of 66 years in individuals heterozygous for the PIZ mutation [29] . The mean age of our patients was 38.43 years at the completion of analysis.…”

Early urinary candidate biomarker discovery in a rat thioacetamide-induced liver fibrosis model

“…A1AT in plasma can cause liver disease in childhood and cirrhosis and/or hepatocellular 354 carcinoma (HCC) in adulthood [68] . The level of A1AT has been found significantly high 355 in liver cirrhosis with hepatitis C viral infection and HCC patients but less in chronic 356 hepatitis C than control subjects and can be used as biomarkers for monitoring the liver 357 diseases [67] .…”

Preclinical Evaluation of Transcriptional Targeting Strategy for Human Hepatocellular Carcinoma in an Orthotopic Xenograft Mouse Model

“…While the mechanism responsible for its complex hepatocarcinogenesis is still under investigation, rapid hepatocellular carcinoma tumor proliferation due to dysregulation of the cell-cycle proteins is clear. Herein, we have taken advantage of the rapid proliferating nature of tumor cells in general and the high levels of hAAT expression found in hepatocellular carcinoma (30)(31)(32) and generated an effective vector system whereby transgene expression is dependent on the activation of two endogenously regulated promoters, i.e., 4ÂApoE/hAAT liver-specific promoter and recombinant human cyclin A2. In the context of oncolytic HSV-1, the 4ÂApoE/hAAT liver-specific promoter has also been shown to drive the expression of complementary sequences of selected miRNAs exclusively in hepatocellular carcinoma (33).…”