TRAIL Receptor Expression and TRAIL-mediated Apoptosis in Hepatocellular Carcinoma

• Main Authors: Chia-hsien Yeh, 葉家賢
• Other Authors: Ping Ning Hsu
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/49349192478869678643

碩士 === 國立臺灣大學 === 免疫學研究所 === 87 === Apoptosis, or programmed cell death, is a process fundamental to the normal development and homeostasis of multicellular organisms. Certain cytokines of the TNF ligand family and their cognate receptors, including TNFR-1 and Fas, are classic triggers of the suicide response. TRAIL (also called TNF-related apoptosis-inducing ligand), a novel member of the TNF ligand family, has been identified in 1995. TRAIL, like Fas ligand, induces rapid apoptosis in transformed cell lines of diverse origin. Unlike FasL, whose transcripts are predominantly restricted to stimulated T cells and sites of immune privilege, TRAIL expression is detected in many normal human tissues, suggesting that TRAIL must not be cytotoxic to most tissues in vivo. However, in recent years, several novel TRAIL receptors were found, all of them belong to the TNF receptor family. Two of the TRAIL receptor, TRAIL-R1/DR4 and TRAIL-R2/DR5 can transduce death signal because they contain death domain in their cytoplasmic region. The other two receptors, might be the inhibitory receptors for TRAIL: TRAIL-R3/TRID/DcR1, which lacks the death domain and is a GPI-anchored membrane protein, and TRAIL-R4/DcR2, which has truncated death domain. A decoy receptor hypothesis for TRAIL mediated tumor killing mechanism was suggested based on the selective expression of DcR1 on normal tissue. In our study, we have tried to use several methods, such as RT-PCR、RNase protection assay and RNA in situ hybridization to characterize the receptor expression pattern in hepatoma cell lines and hepatocellular carcinoma tissue (tumor and non-tumor part). Base on the result of RT-PCR and RNase protection assay, we found that most of the hepatoma cell lines don’t express DcR1, but express the other three TRAIL receptors. Also, the absence of DcR1 in hepatoma cell lines are not correlated with their sensitivity toward TRAIL mediated killing. Meanwhile, DcR1 was detectable in human hepatocellular carcinoma tissue, and RT-PCR showed no significant difference between tumor and nontumor part. Yet results from in situ hybridization studies revealed that there is slightly higher expression of DcR1 on tissue of nontumor part. The resistance to TRAIL mediated apoptosis in hepatoma cell lines are not associated with the expression of intracellular regulatory gene, cFLIP. Jurkat cell activated by PMA plus ionomycin became resistant to TRAIL mediated apoptosis, suggesting that there may be other regulatory mechanisms to modulate the sensitivity to TRAIL. While reagents such as actinomycin D and cyclosporin A can convert cell lines from TRAIL-resistant to TRAIL-sensitive. These results suggest a combinatorial approach of using TRAIL and other chemotherapeutic agents in the treatment of hepatocellular carcinoma.