Department of Pathology, Duke University Medical Center, P.O. Box 3712 D.U.M.C., Durham, NC, 27710, USA.
Breast Cancer Res Treat. 2009 Nov;118(1):197-205. doi: 10.1007/s10549-008-0179-y. Epub 2008 Sep 12.
The axon repulsion factor semaphorin3A (SEMA3A) and its receptor neuropilin-1 (NP-1) are expressed in breast tumor cells, and function as suppressors of tumor cell migration. Based on the knowledge that both SEMA3A and the alpha2beta1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on alpha2beta1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased alpha2 and beta1 integrin levels, and stimulated tumor cell adhesion to the alpha2beta1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased alpha2beta1 levels and collagen adhesion. The ability of SEMA3A to increase tumor cell adhesion to collagen was dependent on both the SEMA3A receptor NP-1 and the glycogen synthase kinase-3. The incubation of breast tumor cells with SEMA3A disrupted the actin cytoskeleton, and reduced both tumor cell migratory and invasive behavior. Importantly, using an alpha2beta1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on alpha2beta1. Our studies indicate that expression of the alpha2beta1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.
轴突排斥因子神经鞘氨醇 3A（SEMA3A）及其受体神经纤毛蛋白-1（NP-1）在乳腺肿瘤细胞中表达，并作为肿瘤细胞迁移的抑制剂发挥作用。基于 SEMA3A 和α2β1 整合素均抑制乳腺肿瘤细胞迁移的知识，我们研究了 SEMA3A 信号对α2β1 整合素表达/功能的影响。SEMA3A 孵育乳腺肿瘤细胞可增加α2 和β1 整合素水平，并刺激肿瘤细胞黏附于α2β1 结合基质蛋白胶原 I。相反，降低乳腺肿瘤细胞中的 SEMA3A 表达会降低α2β1 水平和胶原黏附。SEMA3A 增加肿瘤细胞黏附胶原的能力依赖于 SEMA3A 受体 NP-1 和糖原合酶激酶-3。SEMA3A 孵育乳腺肿瘤细胞会破坏细胞骨架，并降低肿瘤细胞的迁移和侵袭行为。重要的是，我们使用一种α2β1 中和抗体，证明 SEMA3A 抑制肿瘤细胞迁移依赖于α2β1。我们的研究表明，α2β1 整合素的表达，作为乳腺肿瘤生长的转移抑制剂，在乳腺肿瘤细胞中被一种自分泌的 SEMA3A 途径刺激。
