Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Am J Pathol. 2013 Sep;183(3):831-40. doi: 10.1016/j.ajpath.2013.05.010. Epub 2013 Jul 2.
Integrin α7 (ITGA7) is a tumor-suppressor gene that is critical for suppressing the growth of malignant tumors; however, the mechanisms allowing ITGA7 to suppress the growth of cancer cells remain unclear. Herein, we show that ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells. The ITGA7-TIMP3 binding led to a decreased protein level of tumor necrosis factor α, cytoplasmic translocation of NF-κB, and down-regulation of cyclin D1. These changes led to an accumulation of cells in G0/G1 and a dramatic suppression of cell growth. Knocking down TIMP3 or ITGA7/TIMP3 binding interference largely abrogated the signaling changes induced by ITGA7, whereas a mutant ITGA7 lacking TIMP3 binding activity had no tumor-suppressor activity. Interestingly, knocking down ITGA7 ligand laminin β1 enhanced ITGA7-TIMP3 signaling and the downstream tumor-suppressor activity, suggesting the existence of a counterbalancing role between extracellular matrix and integrin signaling. As a result, this report demonstrates a novel and critical signaling mechanism of ITGA7, through the TIMP3/NF-κB/cyclin D1 pathway.
整合素 α7（ITGA7）是一种肿瘤抑制基因，对于抑制恶性肿瘤的生长至关重要；然而，允许 ITGA7 抑制癌细胞生长的机制仍不清楚。在此，我们表明 ITGA7 在前列腺癌细胞中与金属蛋白酶组织抑制剂 3（TIMP3）结合。ITGA7-TIMP3 结合导致肿瘤坏死因子 α 的蛋白水平降低、NF-κB 的细胞质易位和细胞周期蛋白 D1 的下调。这些变化导致细胞在 G0/G1 期积累，并显著抑制细胞生长。敲低 TIMP3 或 ITGA7/TIMP3 结合干扰在很大程度上消除了 ITGA7 诱导的信号变化，而缺乏 TIMP3 结合活性的突变 ITGA7 则没有肿瘤抑制活性。有趣的是，敲低 ITGA7 的配体层粘连蛋白 β1 增强了 ITGA7-TIMP3 信号传导和下游的肿瘤抑制活性，表明细胞外基质和整合素信号之间存在一种平衡作用。因此，本报告通过 TIMP3/NF-κB/细胞周期蛋白 D1 途径，证明了 ITGA7 的一种新的和关键的信号机制。
