Tsuji Shoichiro, Hosotani Ryo, Yonehara Shin, Masui Toshihiko, Tulachan Sidhartha S, Nakajima Sanae, Kobayashi Hiroyuki, Koizumi Masayuki, Toyoda Eiji, Ito Daisuke, Kami Kazuhiro, Mori Tomohiko, Fujimoto Koji, Doi Ryuichiro, Imamura Masayuki
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Int J Cancer. 2003 Aug 10;106(1):17-25. doi: 10.1002/ijc.11170.
Many cancers are resistant to Fas-mediated apoptosis despite the expression of Fas. To investigate the mechanisms by which Fas signals are attenuated, we focused on decoy receptor 3 (DcR3). DcR3 is a soluble receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily and overexpresses in some forms of cancers. Exogenous DcR3 inhibits Fas-mediated apoptosis in Fas-sensitive Jurkat cells. In our study, we examined the expression and function of DcR3 in pancreatic cancers. TaqMan RT-PCR showed that DcR3 mRNA was highly expressed in pancreatic cancer cell lines (71%) and tissues (67%). Its expression significantly correlated with cancer invasion to veins. Western blotting showed that the DcR3 protein was produced and secreted in 4 of 6 cell lines. The protein expressions were compatible with the mRNA expression. Five of 7 pancreatic cancer cell lines became sensitive to agonistic anti-Fas antibody (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNgamma. Four of 7 pancreatic cancer cell lines were inhibited from growing, compared to control cells, when cocultured with membrane-bounded Fas ligand (mFasL) transfected lymphomas for 48 hr after pretreatment with IFNgamma. DcR3 reduced this growth inhibition when added exogenously. Regression analysis showed that the DcR3 expression significantly correlated with the sensitivity to mFasL, and not to CH-11. These results suggest that DcR3 is highly expressed in many pancreatic cancers and endogenous DcR3 blocks the growth inhibition signals mediated by mFasL. DcR3 can be a candidate target molecule for the therapeutic intervention.
尽管许多癌症表达Fas，但它们对Fas介导的细胞凋亡具有抗性。为了研究Fas信号减弱的机制，我们聚焦于诱饵受体3（DcR3）。DcR3是一种针对Fas配体的可溶性受体，属于肿瘤坏死因子受体超家族，在某些癌症中过度表达。外源性DcR3可抑制Fas敏感的Jurkat细胞中Fas介导的细胞凋亡。在我们的研究中，我们检测了DcR3在胰腺癌中的表达及功能。TaqMan RT-PCR结果显示，DcR3 mRNA在胰腺癌细胞系（71%）和组织（67%）中高表达。其表达与癌症侵犯静脉显著相关。蛋白质印迹法显示，6个细胞系中有4个产生并分泌了DcR3蛋白。蛋白质表达与mRNA表达相符。7个胰腺癌细胞系中有5个在经γ干扰素预处理后暴露于抗Fas激动性抗体（CH-11）48小时后，在未上调Fas的情况下，不同程度地对CH-11变得敏感。7个胰腺癌细胞系中有4个在经γ干扰素预处理后与转染了膜结合型Fas配体（mFasL）的淋巴瘤共培养48小时后，与对照细胞相比生长受到抑制。外源性添加DcR3可减轻这种生长抑制。回归分析显示，DcR3表达与对mFasL的敏感性显著相关，而与对CH-11的敏感性无关。这些结果表明，DcR3在许多胰腺癌中高表达，内源性DcR3可阻断mFasL介导的生长抑制信号。DcR3可能是治疗干预的候选靶分子。
