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.
Highlights
Dysregulation of autophagy is important in the pathogenesis of many diseases, including cancer
High Beclin 1, Bcl-xL and Bad levels in chronic hepatitis (CH) and CIRR tissues suggest an interaction between autophagy and apoptosis in the early and intermediate stages of viral hepatitis
Beclin 1 mRNA expression Beclin 1 mRNA levels were significantly lower in hepatocellular carcinoma (HCC) tissues than in CH or CIRR (30.84 ± 17.1 vs 42.65 ± 20.6; P = 0.023 and 45.80 ± 18.4; P = 0.028, respectively), while there was no difference with Cirrhotic tissues surrounding Hepatocellular carcinoma (PHCC) tissues (Figure 1A)
Summary
Dysregulation of autophagy is important in the pathogenesis of many diseases, including cancer. 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. Autophagy (“self-digestion”) is a highly-regulated process, important in cellular homeostasis and involved in the turnover of long-lived proteins and damaged cellular organelles. One of the main factors regulating autophagy is the human beclin-1 gene, located on chromosome 17q21, monoallelically deleted in 40-75% of sporadic breast, prostate, and ovarian tumors [4]. Mice mutant for the gene coding for Beclin 1 have a relatively high incidence of spontaneous tumors, suggesting that a downregulated autophagy may increase the cells’ susceptibility to transformation [5].
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