Department of Pathology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Biol Chem. 2010 Dec 31;285(53):42075-85. doi: 10.1074/jbc.M110.172841. Epub 2010 Oct 25.
A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical β-catenin levels. In addition, Myc, a downstream target of β-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of β-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.
近年来出现的一个主题是，小富含亮氨酸的蛋白聚糖基因家族的成员通过与多种受体酪氨酸激酶（RTKs）相互作用来影响细胞生长，主要通过受体的物理下调，从而剥夺肿瘤细胞的生存信号。核心蛋白聚糖与几种 RTKs 结合并下调其表达，包括肝细胞生长因子的受体 Met。在这里，我们证明了核心蛋白聚糖阻断了由 Met 信号轴介导的几种生物学活性，包括细胞散射、逃避和迁移。这些效应是通过非典型 β-连环蛋白水平的深刻下调介导的。此外，β-连环蛋白的下游靶标 Myc 也被核心蛋白聚糖明显下调，而 Myc 丝氨酸 58 的磷酸化明显诱导。后者已知会使 Myc 不稳定，并将其靶向蛋白酶体降解。我们还发现，使用三种不同的肿瘤异种移植模型系统递送核心蛋白聚糖会下调 Met，并同时抑制 β-连环蛋白和 Myc 水平。我们发现，用近红外染料 IR800 标记的核心蛋白聚糖蛋白核心特异性靶向表达 Met 的肿瘤细胞。即使在注射后 68 小时，核心蛋白聚糖仍被发现存在于肿瘤异种移植物内，与其他组织的结合很少或没有。总的来说，我们的结果表明，一种分泌型蛋白聚糖在抑制肿瘤进展所需的关键致癌因子的表达中发挥作用。
