Chakraborty Sayan, Lakshmanan Manikandan, Swa Hannah L F, Chen Jianxiang, Zhang Xiaoqian, Ong Yan Shan, Loo Li Shen, Akıncılar Semih Can, Gunaratne Jayantha, Tergaonkar Vinay, Hui Kam M, Hong Wanjin
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore.
1] Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore 138673, Singapore [2] Laboratory of Cancer Genomics, Cellular and Molecular Research Division, National Cancer Center Singapore, 11, Hospital drive, Singapore 169610, Singapore.
Nat Commun. 2015 Jan 29;6:6184. doi: 10.1038/ncomms7184.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The identity and role of cell surface molecules driving complex biological events leading to HCC progression are poorly understood, hence representing major lacunae in HCC therapies. Here, combining SILAC quantitative proteomics and biochemical approaches, we uncover a critical oncogenic role of Agrin, which is overexpressed and secreted in HCC. Agrin enhances cellular proliferation, migration and oncogenic signalling. Mechanistically, Agrin's extracellular matrix sensor activity provides oncogenic cues to regulate Arp2/3-dependent ruffling, invadopodia formation and epithelial-mesenchymal transition through sustained focal adhesion integrity that drives liver tumorigenesis. Furthermore, Agrin signalling through Lrp4-muscle-specific tyrosine kinase (MuSK) forms a critical oncogenic axis. Importantly, antibodies targeting Agrin reduced oncogenic signalling and tumour growth in vivo. Together, we demonstrate that Agrin is frequently upregulated and important for oncogenic property of HCC, and is an attractive target for antibody therapy.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。导致HCC进展的复杂生物学事件背后的细胞表面分子的特性和作用尚不清楚，这也是HCC治疗的主要空白。在此，我们结合稳定同位素标记氨基酸定量蛋白质组学（SILAC）和生化方法，揭示了集聚蛋白（Agrin）在HCC中过表达并分泌，发挥关键致癌作用。Agrin增强细胞增殖、迁移和致癌信号传导。从机制上讲，Agrin的细胞外基质传感活性通过维持驱动肝脏肿瘤发生的粘着斑完整性，提供致癌信号来调节肌动蛋白相关蛋白2/3（Arp2/3）依赖性的微丝边缘波动、侵袭伪足形成和上皮-间质转化。此外，Agrin通过低密度脂蛋白受体相关蛋白4（Lrp4）-肌肉特异性酪氨酸激酶（MuSK）信号传导形成关键的致癌轴。重要的是，靶向Agrin的抗体在体内可减少致癌信号传导和肿瘤生长。我们共同证明，Agrin在HCC中经常上调且对其致癌特性很重要，是抗体治疗的一个有吸引力的靶点。
