Tiran Zohar, Oren Anat, Hermesh Chen, Rotman Galit, Levine Zurit, Amitai Hagit, Handelsman Tal, Beiman Merav, Chen Aviva, Landesman-Milo Dalit, Dassa Liat, Peres Yair, Koifman Cynthia, Glezer Sarit, Vidal-Finkelstein Rinat, Bahat Kobi, Pergam Tania, Israel Cylia, Horev Judith, Tsarfaty Ilan, Ayalon-Soffer Michal
Compugen Ltd., Tel Aviv, Israel.
Clin Cancer Res. 2008 Jul 15;14(14):4612-21. doi: 10.1158/1078-0432.CCR-08-0108.
The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), are involved in a wide range of biological activities, including cell proliferation, motility, invasion, and angiogenesis. The HGF/SF-Met signaling pathway is frequently activated in a variety of cancers, and uncontrolled Met activation correlates with highly invasive tumors and poor prognosis. In this study, we investigated the inhibitory effect of a novel soluble splice variant of Met on the HGF/SF-Met pathway.
Using our alternative splicing modeling platform LEADS, we have identified a novel splice variant of the Met receptor, which encodes a truncated soluble form of the receptor. This variant was produced as a recombinant Fc-fused protein named Cgen-241A and was tested in various cell-based assays representing different outcomes of the HGF/SF-Met pathway.
Cgen-241A significantly inhibited HGF/SF-induced Met phosphorylation as well as cell proliferation and survival. In addition, Cgen-241A showed a profound inhibitory effect on cell scattering, invasion, and urokinase up-regulation. The inhibitory effects of Cgen-241A were shown in multiple human and nonhuman cell types, representing different modes of Met activation. Furthermore, Cgen-241A showed direct binding to HGF/SF.
Taken together, our results indicate that Cgen-241A is a potent antagonist of the HGF/SF-Met pathway, underlining its potential as a therapeutic agent for the treatment of a wide variety of human malignancies that are dependent on this pathway.
Met受体酪氨酸激酶及其配体肝细胞生长因子/分散因子（HGF/SF）参与多种生物学活性，包括细胞增殖、运动、侵袭和血管生成。HGF/SF-Met信号通路在多种癌症中经常被激活，而不受控制的Met激活与高侵袭性肿瘤和不良预后相关。在本研究中，我们研究了一种新型Met可溶性剪接变体对HGF/SF-Met通路的抑制作用。
利用我们的可变剪接建模平台LEADS，我们鉴定出了Met受体的一种新型剪接变体，其编码受体的截短可溶性形式。该变体作为一种名为Cgen-241A的重组Fc融合蛋白产生，并在代表HGF/SF-Met通路不同结果的各种基于细胞的试验中进行了测试。
Cgen-241A显著抑制HGF/SF诱导的Met磷酸化以及细胞增殖和存活。此外，Cgen-241A对细胞分散、侵袭和尿激酶上调显示出显著的抑制作用。Cgen-241A的抑制作用在多种人类和非人类细胞类型中得到证实，代表了不同的Met激活模式。此外，Cgen-241A显示出与HGF/SF直接结合。
综上所述，我们的结果表明Cgen-241A是HGF/SF-Met通路的有效拮抗剂，突显了其作为治疗多种依赖该通路的人类恶性肿瘤的治疗剂的潜力。
