Autophagy and apoptosis-related genes in chronic liver disease and hepatocellular carcinoma

Abstract

BackgroundDysregulation of autophagy is important in the pathogenesis of many diseases, including cancer. Several aspects of the biological role of autophagy are however still unclear and the relationship between apoptosis and autophagy, particularly in the liver has yet to be thoroughly explored. In this study we evaluated the expression of Beclin 1 (one of the main autophagocytic agents, which bridges autophagy, apoptosis and both differentiation), and both pro- (Bad, Bax) and anti-apoptotic (Bcl-2, Bcl-xL) factors in liver samples from patients with different stages of liver disease.MethodsThe study concerned 93 patients from 49 cases of chronic hepatitis (CH) (30 HCV and 19 HBV-related), 13 of cirrhosis (CIRR) (10 HCV and 3 HBV-related), 21 of hepatocellular carcinoma (both HCC and peritumoral tissues [PHCC]), and 10 controls (CONTR). Real-time PCR and Western blotting were used to measure mRNA and protein expression levels.ResultsBeclin 1 mRNA levels were lower in HCC than in CH (P = 0.010) or CIRR (P = 0.011), and so were the Bcl-xL transcripts (P < 0.0001). Bad mRNA levels were higher in CH and CIRR than in CONTR, while Bax transcripts were increased in all tissues (P = 0.036). PHCC expressed the highest Bcl-2 mRNA levels. HBV-related CH tissues showed significantly higher Bcl-xL and Bad mRNA levels than HCV-related CH (P = 0.003 and P = 0.016, respectively).ConclusionsHigh Beclin 1, Bcl-xL and Bad levels in CH and CIRR tissues suggest an interaction between autophagy and apoptosis in the early and intermediate stages of viral hepatitis. In HCC these processes seem to be downregulated, probably enabling the survival and growth of neoplastic hepatocytes.

SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway

“…For instance, a high incidence of spontaneous HCC is observed in mice in which homozygous Beclin-1 is knocked out and Atg5 or Atg7 is deleted [20; 21]. In addition, Beclin-1 expression is decreased in human HCC tissues and is positively associated with longer time to recurrence and longer overall survival [22]. Similarly, the downregulation of LC3 expression is detected in HCC, and LC3 expression is correlated with a longer overall survival of HCC patients, particularly those in advanced stages, suggesting that LC3 is an independent predictor of prognosis in patients with HCC [23].…”

Impaired autophagy response in human hepatocellular carcinoma

“…Cellular autophagy, which is maintained during chronic liver injury, may play an important role in the sustainment of chronic liver disease and cancer development (Rautou et al, 2010; Kotsafti et al, 2012; Raitou et al, 2011). In this regard, there is evidence to suggest that mice with deletion of autophagy related genes, i.e.…”

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

“…Therefore, further studies are needed to clarify the role of autophagy in the process of liver fibrosis before a therapeutic approach targeting autophagy can be used. Previous studies showed that the mRNA levels of Beclin 1 were lower in HCC tissues than in chronic hepatitis or cirrhosis [86,87]. In addition, other in vivo and in vitro studies supported that the autophagic pathway was inhibited in HCC [71,72,[88][89][90].…”