Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
Department of Oncology, CHUV and University of Lausanne, Switzerland and Ludwig Institute for Cancer Research, Lausanne, Switzerland.
Sci Rep. 2018 Jun 22;8(1):9531. doi: 10.1038/s41598-018-27739-w.
The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.
转录因子 PROX1 对发育和细胞命运特化至关重要。其在癌症中的功能是依赖于上下文的，因为已经表明 PROX1 具有致癌和肿瘤抑制作用。在这里，我们表明 PROX1 通过结合和抑制 MMP14 启动子的活性来抑制参与血管生成和癌症侵袭的金属蛋白酶 MMP14 的转录。体内敲除小鼠皮肤淋巴管和人 LECs 中的 Prox1 增加了 MMP14 的表达。在表达高水平内源性 PROX1 的肝癌细胞系中，其沉默增加了 MMP14 的表达和 MMP14 依赖性的 3D 侵袭。此外，PROX1 的异位表达降低了 MMP14 依赖性乳腺癌细胞的 3D 侵袭性和血管内皮细胞的血管生成发芽，同时抑制了 MMP14。我们的研究揭示了癌细胞侵袭和内皮细胞特化的新转录调控机制。
