Abstract
The cytokine tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis in liver cancer cells but not in normal liver cells. Therefore, TRAIL got credited to play a role in hepatocellular carcinoma (HCC) development and progression. Impaired expression of TRAIL in HCC cells and sequence variations in the TRAIL promoter may facilitate development, growth, and spread . The TRAIL promoter was sequenced from liver tissue of 93 patients undergoing partial liver resection (PRT) or liver transplantation (LT) for HCC. TRAIL mRNA expression was investigated by quantitative real‐time PCR. A variant ‐1573T>C (single‐nucleotide polymorphism; C, cytosine) SNP was characterized by electron mobility shift assay and supershift assays. Functionality of the ‐1573T>C SNP was analyzed in reporter gene assays and cell migration assays. In approximately 30% of HCC samples, a loss‐of‐function shift of the binding pattern due to a ‐1573T>C SNP was found within the human TRAIL promoter. Correlation analysis revealed significantly lower TRAIL expression in HCC samples with the ‐1573C sequence (P ≤ 0.05). Reporter gene assays revealed significantly reduced inducibility of the TRAIL promoter due to the ‐1573C sequence. The variant ‐1573C sequence impaired not only binding of transcription factors but also expression of TRAIL. Interestingly, this impairment resulted in enhanced migration activity and colony formation of the liver tumor cells. Our findings suggest that loss of function of the human TRAIL promoter due to the ‐1573T>C SNP leads to reduced expression and impaired inducibility of TRAIL, with the consequence of enhanced growth and migration of tumor cells, ultimately resulting in the progression of the HCC.
Highlights
Hepatocellular carcinoma (HCC) is a severe health burden, as it is one of the most common cancers worldwide and one of the first three causes of cancer-related mortality [1, 2]
Nucleotide exchange from T to C leads to a loss of function of the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promoter in reporter gene assays and demonstrates the indispensability of this element for the TRAIL promoter activity, the inducibility of TRAIL in response to apoptosis-inducing cytokines (Fig. 3)
The -1573T>C SNP results in a reduction in TRAIL mRNA expression (Fig. 2A), that probably enhances the tissue’s susceptibility to tumor development and progression. These considerations are supported by the findings of studies demonstrating that apoptosis is impaired by dysregulation of TRAIL and TRAIL receptors in several other tumor entities [32, 33] and that TRAIL receptors influence the pathogenesis of several liver diseases
Summary
Hepatocellular carcinoma (HCC) is a severe health burden, as it is one of the most common cancers worldwide and one of the first three causes of cancer-related mortality [1, 2]. The incidence of HCC caused by hepatitis C (HCV)-related liver cirrhosis is expected to decrease because of more efficient therapeutic options [3, 4], this decrease will be balanced by a cumulative burden of alcoholic steatohepatitis (ASH) or nonalcoholic steatohepatitis (NASH) as precancerous states [5]. Liver transplantation for HCC is characterized by a good long-term outcome, the tumor recurs in a certain percentage of patients [9]. The molecular process of HCC development implies the activation of oncogenes and the repression of apoptosis;
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