Slit-2 induces a tumor-suppressive effect by regulating β-catenin in breast cancer cells
Slit-2 induces a tumor-suppressive effect by regulating β-catenin in breast cancer cells
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DOI：
10.1074/jbc.m800679200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Ganju, Ramesh K.
中科院分区：
文献类型：
--
作者：
Prasad, Anil;Paruchuri, Vikram;Ganju, Ramesh K.
SLIT-2被认为是一个候选的肿瘤抑制基因，因为它经常在各种癌症中由于其启动子区域的超甲基化和等位基因丢失而失活。然而，其抑瘤作用的确切机制尚未阐明。在这里，我们观察到Slit-2过表达的乳腺癌细胞在体外条件下与对照细胞相比表现出降低的增殖和迁移能力。这些结果在小鼠模型系统中得到体内证实。与注射MCF-7/VC细胞的小鼠相比，在不存在和存在雌激素的情况下，注射MCF-7/Slit-2细胞的小鼠显示肿瘤大小减少60-70%。在进一步阐明后，我们观察到Slit-2通过协调调节β-连环蛋白和PI 3 K信号通路以及通过增强β-连环蛋白/E-钙粘蛋白介导的细胞-细胞粘附来介导肿瘤抑制作用。我们的研究首次揭示了Slit-2过表达乳腺癌细胞通过β-连环蛋白调节的新机制表现出肿瘤抑制能力。
SLIT-2 is considered as a candidate tumor suppressor gene, because it is frequently inactivated in various cancers due to hypermethylation of its promoter region and allelic loss. However, the exact mechanism of its tumor-suppressive effect has not been elucidated. Here, we observed that Slit-2-overexpressing breast cancer cells exhibited decreased proliferation and migration capabilities compared with control cells under in vitro conditions. These results were confirmed in vivo in mouse model systems. Mice injected with MCF-7/Slit-2 cells showed a 60-70% reduction in tumor size compared with mice injected with MCF-7/VC cells both in the absence and presence of estrogen. Upon further elucidation, we observed that Slit-2 mediates the tumor-suppressive effect via a coordinated regulation of the beta-catenin and PI3K signaling pathways and by enhancing beta-catenin/E-cadherin-mediated cell-cell adhesion. Our study for the first time reveals that Slit-2-overexpressing breast cancer cells exhibit tumor suppressor capabilities through the novel mechanism of beta-catenin modulation.