Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca2+-NFAT1 Axis
Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca2+-NFAT1 Axis
复制标题
ABAT 介导的 GABA 能系统的丧失通过激活 Ca2 -NFAT1 轴促进基底样乳腺癌进展
DOI：
10.7150/thno.29407
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Dong, Chenfang
中科院分区：
文献类型：
--
作者：
Chen, Xingyu;Cao, Qianhua;Dong, Chenfang
基底细胞样乳腺癌（BLBC）是最积极的亚型，临床效果不佳，然而，在BLBC的侵略性的分子机制仍然知之甚少。方法：γ-氨基丁酸转氨酶（ABAT）对GABA受体，Ca 2 + -NFAT 1轴，和癌细胞行为的影响进行了评估钙离子成像，蛋白质印迹，免疫染色，集落形成，迁移和侵袭试验。我们通过荧光素酶报告基因和ChIP分析阐明了ABAT和Snail之间的关系。ABAT表达对BLBC细胞的影响通过体外和体内肿瘤发生和肺转移小鼠模型来确定。结果：我们发现，与其他亚型相比，ABAT在BLBC中显著降低。从机制上讲，ABAT表达下调，由于蜗牛介导的抑制，导致GABA的生产增加。GABA可通过激活GABA-A受体（GABA（A）），提高BLBC细胞内Ca ~（2+）浓度，从而有效激活NFAT 1。ABAT的表达抑制了BLBC细胞的体外和体内致瘤性和转移。因此，ABAT的丧失通过激活Ca 2 +-NFAT 1轴而促进BLBC的侵袭性。在乳腺癌患者中，ABAT表达的损失与大肿瘤大小，高级别和转移趋势，生存率差，化疗resistance.Conclusions：我们的研究结果提供了潜在的分子细节BLBC的侵略性行为。Snail介导的BLBC中ABAT表达的下调通过激活GABA介导的Ca 2 +-NFAT 1轴而提供肿瘤发生和转移优势。因此，我们的研究结果已经确定了这种具有挑战性的疾病的潜在预后指标和治疗靶点。
Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood.Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca2+ -NFAT1 axis, and cancer cell behavior were assessed by Ca2+ imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model.Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca2+ concentration by activating GABA-A receptor (GABA(A)), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca2+-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance.Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca2+-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease.