Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Oncogene. 2011 Aug 25;30(34):3682-93. doi: 10.1038/onc.2011.85. Epub 2011 Mar 28.
Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression. By exogenous SCUBE3 treatment or knockdown of SCUBE3 expression, we found that SCUBE3 could promote lung cancer cell mobility and invasiveness. Knockdown of SCUBE3 expression also suppressed tumorigenesis and cancer metastasis in vivo. The secreted SCUBE3 proteins were cleaved by gelatinases (matrix metalloprotease-2 (MMP-2) and MMP-9) in media to release two major fragments: the N-terminal epidermal growth factor-like repeats and the C-terminal complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. Both the purified SCUBE3 protein and the C-terminal CUB domain fragment, bound to transforming growth factor-β (TGF-β) type II receptor through the C-terminal CUB domain, activated TGF-β signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation, the increase of Smad2/3 transcriptional activity and the upregulation of the expression of target genes involved in EMT and cancer progression (such as TGF-β1, MMP-2, MMP-9, plasminogen activator inhibitor type-1, vascular endothelial growth factor, Snail and Slug), thus promoting cancer cell mobility and invasion. In conclusion, in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-β type II receptor, which could regulate TGF-β receptor signaling and modulate EMT and cancer progression.
信号肽-CUB-EGF 样结构域蛋白 3（SCUBE3）是一种分泌性糖蛋白，在肺癌肿瘤组织中过度表达，与肺癌细胞系模型中的侵袭能力相关。这些观察结果表明，SCUBE3 可能在肺癌进展中发挥作用。通过外源性 SCUBE3 处理或 SCUBE3 表达的敲低，我们发现 SCUBE3 可以促进肺癌细胞的迁移和侵袭性。SCUBE3 表达的敲低也抑制了体内的肿瘤发生和癌症转移。分泌的 SCUBE3 蛋白被明胶酶（基质金属蛋白酶-2（MMP-2）和 MMP-9）在介质中切割，释放两个主要片段：N 端表皮生长因子样重复序列和 C 端补体蛋白 C1r/C1s、Uegf 和 Bmp1（CUB）结构域。纯化的 SCUBE3 蛋白和 C 端 CUB 结构域片段都通过 C 端 CUB 结构域与转化生长因子-β（TGF-β）Ⅱ型受体结合，激活 TGF-β 信号并引发上皮-间充质转化（EMT）。这个过程包括诱导 Smad2/3 磷酸化、增加 Smad2/3 转录活性以及上调 EMT 和癌症进展相关的靶基因（如 TGF-β1、MMP-2、MMP-9、纤溶酶原激活物抑制剂 1、血管内皮生长因子、Snail 和 Slug）的表达，从而促进癌细胞的迁移和侵袭。总之，在肺癌细胞中，SCUBE3 可以作为 TGF-β Ⅱ型受体的内源性自分泌和旁分泌配体，调节 TGF-β 受体信号并调节 EMT 和癌症进展。
