GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling.
GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling.
复制标题
DOI：
10.1038/s41598-018-27864-6
复制
发表时间：
2018-06-22
影响因子：
4.6
通讯作者：
Baeg GH
中科院分区：
文献类型：
--
作者：
Khanna P;Lee JS;Sereemaspun A;Lee H;Baeg GH
JAK/STAT信号转导失调与乳腺癌转移有关，这与高复发风险相关。然而，JAK/STAT信号介导的乳腺肿瘤发生的机制知之甚少。在这里，我们发现GRAMD 1B表达在IL-6上上调，但在乳腺癌MDA-MB-231细胞中用JAK 2抑制剂AG 490处理后下调。值得注意的是，Gramd 1b敲低引起细胞的形态学变化，其特征在于形成膜皱褶和突起，暗示其在细胞迁移中的作用。一致地，GRAMD 1B抑制显著增强细胞迁移，具有GTP酶的Rho家族的水平的增加。我们还发现，Gramd 1b敲低介导的促迁移表型与JAK 2/STAT 3和Akt激活相关，并且JAK 2或Akt抑制有效地抑制了表型。有趣的是，AG 490剂量依赖性地增加p-Akt水平，并且我们的上位性分析表明JAK/STAT抑制对p-Akt的影响是通过调节GRAMD 1B表达。综上所述，我们的研究结果表明，GRAMD 1B是一种关键的信号分子，其功能是通过否定JAK/STAT和Akt信号来抑制乳腺癌中的细胞迁移，为其作为乳腺癌中的新型生物标志物的发展提供了基础。
Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.
登录
查看更多内容
影响因子：
4.8
作者：
Chang, Qing;Bournazou, Eirini;Bromberg, Jacqueline
通讯作者：
Bromberg, Jacqueline
影响因子：
5.7
作者：
Bid HK;Roberts RD;Manchanda PK;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
5.2
作者：
Chung SS;Giehl N;Wu Y;Vadgama JV
通讯作者：
Vadgama JV
影响因子：
11.2
作者：
Leslie, K;Lang, C;Bromberg, J
通讯作者：
Bromberg, J
影响因子：
10.5
作者：
Baeg, GH;Zhou, R;Perrimon, N
通讯作者：
Perrimon, N