Liu Kebin, Abrams Scott I
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2003 Jun 15;170(12):6329-37. doi: 10.4049/jimmunol.170.12.6329.
Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma, whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
γ干扰素被认为在抗肿瘤反应的调节中至关重要。然而，恶性细胞对γ干扰素的反应程度可能会对抗肿瘤反应的整体疗效产生深远影响。在本研究中，我们探讨了γ干扰素使人类原发性和转移性结肠癌细胞对Fas介导的凋亡产生不同敏感性的分子基础。为此，我们在基因组水平分析了γ干扰素诱导的基因表达，随后分析了与γ干扰素和Fas介导的信号传导相关的特定基因的表达和功能。我们发现，尽管这两种细胞群体在基因组水平上对γ干扰素的反应表现出相似的基因表达谱，但γ干扰素调节基因的表达强度在原发性肿瘤中要大得多。值得注意的是，有两个基因，一个参与γ干扰素介导的信号传导，即干扰素共有序列结合蛋白（ICSBP），另一个参与Fas介导的信号传导，即半胱天冬酶-1，在这两种细胞系中明显表现出不同的诱导情况。在原发性肿瘤细胞中，ICSBP和半胱天冬酶-1的表达在γ干扰素刺激下强烈诱导，而在转移性肿瘤细胞中则弱至无法检测到。功能研究表明，半胱天冬酶-1和ICSBP在γ干扰素致敏后均参与Fas介导的凋亡，但通过两条不同的途径进行。本研究还首次报道了ICSBP在具有促凋亡特性的非造血肿瘤中的表达。总体而言，在人类结肠癌细胞模型中，我们确定了两个γ干扰素调节基因ICSBP和半胱天冬酶-1在Fas介导的死亡机制中的重要功能作用。
