a Department of Neurosurgery, Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710004, Shaanxi, People's Republic of China.
b Department of Neurosurgery, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, Shaanxi, People's Republic of China.
Biochem Cell Biol. 2019 Aug;97(4):488-496. doi: 10.1139/bcb-2018-0114. Epub 2018 Dec 11.
Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator for steroid receptors and other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in glioma progression remains unknown. Here, in this study, we report that SRC-1 is upregulated in the vessels of human glioma and exerts important regulatory functions. Specifically, SRC-1 expression significantly enhanced basic fibroblast growth factor (bFGF)-mediated angiogenesis in vivo. Downregulating of SRC-1 expression suppressed endothelial cell migration and tube formation in vitro and upregulated the expression of pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metallopeptidase (MMP)-9 in glioma cells. These SRC-1-mediated effects were dependent on the activation of polyomavirus enhancer activator 3 (PEA3) transcriptional activity. VEGF and VEGF inducer GS4012 induced the direct binding of SRC-1 and PEA3 in glioma cells, and PEA3 could directly bind with and promoter under GS4012 treatment in glioma cell. The expression of pro-angiogenic factors induced by SRC-1 was abrogated by sh-PEA3 knockdown. Taken together, these novel outcomes indicated that SRC-1 modulated endothelial cell (EC) function and facilitated a pro-angiogenic microenvironment through PEA3 signaling. Moreover, a combination of targeting SRC-1 and PEA3 signaling in glioma could be a promising strategy for suppressing tumor angiogenesis.
类固醇受体共激活因子 1（SRC-1）是类固醇受体和其他转录因子的转录共激活因子。已经表明 SRC-1 在乳腺癌和前列腺癌的进展中发挥重要作用。然而，其在神经胶质瘤进展中的作用尚不清楚。在本研究中，我们报告 SRC-1 在人神经胶质瘤的血管中上调，并发挥重要的调节功能。具体而言，SRC-1 表达显著增强了体内碱性成纤维细胞生长因子（bFGF）介导的血管生成。下调 SRC-1 表达抑制了内皮细胞迁移和体外管形成，并上调了血管内皮生长因子（VEGF）和基质金属蛋白酶（MMP）-9 等促血管生成因子在神经胶质瘤细胞中的表达。这些 SRC-1 介导的效应依赖于多瘤病毒增强子激活物 3（PEA3）转录活性的激活。VEGF 和 VEGF 诱导剂 GS4012 诱导 SRC-1 和 PEA3 在神经胶质瘤细胞中的直接结合，并且 PEA3 可以在 GS4012 处理下直接与 和 启动子结合在神经胶质瘤细胞中。SRC-1 诱导的促血管生成因子的表达被 sh-PEA3 敲低所阻断。总之，这些新的结果表明，SRC-1 通过 PEA3 信号调节内皮细胞（EC）功能并促进促血管生成微环境。此外，针对神经胶质瘤中的 SRC-1 和 PEA3 信号的联合靶向可能是抑制肿瘤血管生成的有前途的策略。
