Decreased TRAIL expression is a dominant feature of human HCC
Aims: The proapoptotic molecule TRAIL has gained attention for its ability to induce apoptosis in liver cancer cells without damaging normal liver cells. It may play an important role in preventing development and outgrowth of liver tumors. HCC is recognized as one of the most common and most malignant cancers worldwide. However, the molecular mechanisms causing the sequence of events of its development are still poorly understood. To clarify the clinical implication of TRAIL for HCC development, the expression of TRAIL was analysed in a large series of human HCCs.
Methods: 70 patients undergoing partial liver resection or LTx because of HCC were included. HCC probes and surrounding non-tumorous liver tissue was macrodissected and analysed for expression of TRAIL by qrt-PCR. The same was done in several hepatoma cell lines. TRAIL expression was correlated with ethiology of liver disease, tumor spread and AFP levels before surgery. Liver tissue with fibrosis or cirrhosis not developing HCC as well as benign liver tumors were used as control.
Results: Expression of the TRAIL mRNA was reduced or abolished in 60% of all tumors compared to surrounding non-tumorous liver tissue. Seperated by ethiology of liver disease, decreased levels of TRAIL correlate with Hepatitis C virus infection in 2/3 of cases. As well, female patients with NASH display decreased TRAIL expression in 80% of all NASH-based tumors. Intrestingly, cirrhotic livers with background of autoimmune disorders of the liver (AIH, PBC, PSC) do rarely show HCC development in general and corresponding liver tissue rather shows normal or increased TRAIL levels on the cell surface. Low TRAIL-expression levels do not significantly correlate with higher AFP levels.
Conclusions: Our results suggest, that TRAIL protein loss goes in line with HCC development. Predominately Hepatitis C virus-induced mechanisms result in liver tumor development, as well as alimentary liver disorders. Loss of TRAIL expression seems to influence aggressiveness of tumor growth. Furthermore, TRAIL expression is not compromised in those liver diseases rarely developing HCCs such as autoimmune liver diseases. Thus, a decrease in TRAIL expression may significantly contribute in HCC development and growth.