CD95 Promotes Tumour Growth

Marcus E. Peter et al. 2010. Nature. 465:492-496.

Student: Tsan-Tzu Yang (楊璨滋)                                          Time: 13:10-14:00, Sep. 15, 2010

Commentator: Dr. Hsiao-Sheng Liu (劉校生博士)              Place: Room 601

Abstract

Down-regulation of death receptor CD95, a regulator for homeostasis of immune system through apoptosis, prevents cells from cell death or promotes tumor evasion (1). However, several studies indicated that CD95 or its ligand (CD95L) is elevated in cancer patients (2). In this study, the authors demonstrated that CD95 had non-apoptotic activity and promoted tumor growth. Using lentiviral-based short-hairpin RNA (shRNA) against CD95 or CD95L, the results showed that knockdown of CD95 or CD95L reduced the growth of cancer cell lines derived from ovarian (HeyA8 and SKOV3.ip1), colon (HCT116), renal (CAKI-1), breast (MCF7), and liver cancers (HepG2). To investigate whether CD95 facilitates outgrowth of ovarian cancer in vivo, SKOV3.ip1 cells were infected with CD95 shRNA and then injected into nude mice. In SKOV3.ip1 R6-derived tumors, the results of Ki67, CD31 and TUNEL staining indicated that vascularization and apoptosis were reduced in the absence of CD95 signaling. Abrogation of CD95 or neutralizing CD95L antibody attenuated the growth of SKOV3.ip1 tumors. Using Kras/Pten mutant mice, which carrying loxP sites inCD95 gene, the incidence of tumor growth was higher in ovarian expressing wild-type (WT) CD95 than in the Cre-injected CD95-knockout ovarian. After partial hepatectomy, the WT and liver-specific CD95-knockout mice were detected BrdU expression, and the result showed that CD95-knockout mice had a defect in liver regeneration. CD95-deficient mice were treated with diethylnitrosamine to induce hepatocellular carcinoma. Authors observed that lacking CD95 in liver reduced the size of hepatocellular carcinoma. As compared to WT, JNK and Jun phosphorylation were down-regulated in CD95-deficient hepatocellular carcinoma. Blockade of CD95 up-regulated the phosphorylation of JNK and Jun and down-regulated the activation of caspase-3. Taken together, these results clearly demonstrate the tumorigenic activity of CD95 is mediated by a cell survival-promoting pathway involving JNK and Jun.

References

1. Nagata, S., et al. 2009. The many roles of FAS receptor signaling in the immune system. Immunity. 30:180-192.

2. Barnhart, B. C., et al. 2004. CD95 ligand induces motility and invasiveness of apoptosis resistant tumor cells. EMBO J. 23:3175-3185.