Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Urology. 2012 Apr;79(4):966.e1-7. doi: 10.1016/j.urology.2011.12.011. Epub 2012 Feb 15.
To investigate the role of transforming growth factor-β-induced (TGFBI) in metastasis of renal cell carcinoma (RCC) and the associations between TGFBI expression and von Hippel-Lindau (VHL) status.
In null type VHL cells stably transfected with the VHL vector, the expression of VHL in cells with wild type VHL was decreased by siRNA. We investigated the effects of hypoxia-inducible transcription factor (HIF) on TGFBI in RCC cells by decreasing the expression levels of HIF-1α and HIF-2α through siRNA. The secretion of transforming growth factor-β1 (TGF-β1) in RCC cells with different VHL status was analyzed by enzyme-linked immunosorbent assay. The role of TGFBI in metastasis and the effect of VHL activation on TGFBI-induced adhesion, migration, and invasion in RCC cells were examined using matrigel, chemotaxis, and the transwell system, respectively.
Our results suggested that TGF-β1 and TGFBI might be targets of VHL, and the suppression of TGFBI by VHL is not by way of the HIF-1α or HIF-2α pathway. The expression of TGFBI was significantly enhanced by TGF-β1 in VHL-inactive RCC cells compared with VHL-active cells. In addition, these results indicate that TGFBI participated in the adhesion, migration, and invasion of RCC cells, which are dependent on the inactivation of VHL.
The results of the present study suggest that TGFBI-promoted metastasis of RCC cells depends on inactivation of the VHL tumor suppressor and that TGFBI could be a therapeutic target against RCC in the future.
研究转化生长因子-β诱导（TGFBI）在肾细胞癌（RCC）转移中的作用，以及 TGFBI 表达与 von Hippel-Lindau（VHL）状态之间的关系。
在稳定转染 VHL 载体的 VHL 缺失型细胞中，通过 siRNA 降低野生型 VHL 细胞中 VHL 的表达。我们通过 siRNA 降低 HIF-1α 和 HIF-2α 的表达水平，研究缺氧诱导转录因子（HIF）对 RCC 细胞中 TGFBI 的影响。通过酶联免疫吸附试验分析不同 VHL 状态的 RCC 细胞中转化生长因子-β1（TGF-β1）的分泌情况。利用基质胶、趋化和 Transwell 系统分别检测 TGFBI 在 RCC 细胞转移中的作用以及 VHL 激活对 TGFBI 诱导的 RCC 细胞黏附、迁移和侵袭的影响。
结果表明，TGF-β1 和 TGFBI 可能是 VHL 的靶标，而 VHL 对 TGFBI 的抑制不是通过 HIF-1α 或 HIF-2α 途径。与 VHL 活性细胞相比，TGF-β1 可显著增强 VHL 失活的 RCC 细胞中 TGFBI 的表达。此外，这些结果表明，TGFBI 参与了 RCC 细胞的黏附、迁移和侵袭，这依赖于 VHL 的失活。
本研究结果提示，TGFBI 促进 RCC 细胞转移依赖于 VHL 肿瘤抑制因子的失活，TGFBI 可能成为未来治疗 RCC 的靶点。
