College of Health and Life Science, Hamad bin Khalifa University, Doha, Qatar; Calcium Signaling Group, Research Department, Weill Cornell Medicine, Doha, Qatar.
Calcium Signaling Group, Research Department, Weill Cornell Medicine, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, United States.
Cell Calcium. 2023 Sep;114:102779. doi: 10.1016/j.ceca.2023.102779. Epub 2023 Jun 28.
Store-operated calcium entry (SOCE) contributes to several physiological and pathological conditions including transcription, secretion, immunodeficiencies, and cancer. SOCE has been shown to be important for breast cancer cell migration where knockdown of SOCE components (STIM1 or Orai1) decreases cancer metastasis. Here we show unexpectedly that complete knockout of STIM1 (STIM1-KO) using gene editing in metastatic MDA-MB-231 breast cancer cells results in faster migration and enhanced invasion capacity. In contrast, Orai1-KO cells, which have similar levels of SOCE inhibition as STIM1-KO, migrate slower than the parental cell line. This shows that the enhanced migration phenotype of STIM1-KO cells is not due to the loss of Ca entry through SOCE, rather it involves transcriptional remodeling as elucidated by RNA-seq analyses. Interestingly, NFAT1 is significantly downregulated in STIM1-KO cells and overexpression of NFAT1 reversed the enhanced migration of STIM1-KO cells. STIM1 knockout in other breast cancer cells, independent of their metastatic potential, also enhanced cell migration while reducing NFAT1 expression. These data argue that in breast cancer cells STIM1 modulates NFAT1 expression and cell migration independently of its role in SOCE.
钙库操纵性钙内流（SOCE）参与多种生理和病理状况，包括转录、分泌、免疫缺陷和癌症。SOCE 已被证明对乳腺癌细胞迁移很重要，敲低 SOCE 成分（STIM1 或 Orai1）会降低癌症转移。在这里，我们出人意料地发现，使用基因编辑在转移性 MDA-MB-231 乳腺癌细胞中完全敲除 STIM1（STIM1-KO）会导致更快的迁移和增强的侵袭能力。相比之下，Orai1-KO 细胞的 SOCE 抑制水平与 STIM1-KO 相似，但迁移速度比亲本细胞系慢。这表明 STIM1-KO 细胞增强的迁移表型不是由于通过 SOCE 丧失 Ca 内流引起的，而是涉及 RNA-seq 分析阐明的转录重塑。有趣的是，NFAT1 在 STIM1-KO 细胞中显著下调，过表达 NFAT1 逆转了 STIM1-KO 细胞的增强迁移。STIM1 在其他乳腺癌细胞中的敲除，与其转移潜力无关，也增强了细胞迁移，同时降低了 NFAT1 的表达。这些数据表明，在乳腺癌细胞中，STIM1 独立于其在 SOCE 中的作用调节 NFAT1 表达和细胞迁移。
