Laboratoire de Physiologie Cellulaire, JE 2530, UFR Sciences, 33 rue Saint-Leu, Université de Picardie Jules Verne, Amiens, France.
J Cell Physiol. 2012 Dec;227(12):3837-46. doi: 10.1002/jcp.24095.
Breast cancer (BC) has a poor prognosis due to its strong metastatic ability. Accumulating data present ether à go-go (hEag1) K(+) channels as relevant player in controlling cell cycle and proliferation of non-invasive BC cells. However, the role of hEag1 in invasive BC cells migration is still unknown. In this study, we studied both the functional expression and the involvement in cell migration of hEag1 in the highly metastatic MDA-MB-231 human BC cells. We showed that hEag1 mRNA and proteins were expressed in human invasive ductal carcinoma tissues and BC cell lines. Functional activity of hEag1 channels in MDA-MB-231 cells was confirmed using astemizole, a hEag1 blocker, or siRNA. Blocking or silencing hEag1 depolarized the membrane potential and reduced both Ca(2+) entry and MDA-MB-231 cell migration without affecting cell proliferation. Recent studies have reported that Ca(2+) entry through Orai1 channels is required for MDA-MB-231 cell migration. Down-regulation of hEag1 or Orai1 reduced Ca(2+) influx and cell migration with similar efficiency. Interestingly, no additive effects on Ca(2+) influx or cell migration were observed in cells co-transfected with sihEag1 and siOrai1. Finally, both Orai1 and hEag1 are expressed in invasive breast adenocarcinoma tissues and invaded metastatic lymph node samples (LNM(+)). In conclusion, this study is the first to demonstrate that hEag1 channels are involved in the serum-induced migration of BC cells by controlling the Ca(2+) entry through Orai1 channels. hEag1 may therefore represent a potential target for the suppression of BC cell migration, and thus prevention of metastasis development.
乳腺癌（BC）由于其较强的转移能力而预后不良。越来越多的数据表明，ether à go-go（hEag1）K(+) 通道是控制非侵袭性 BC 细胞周期和增殖的相关因子。然而，hEag1 在侵袭性 BC 细胞迁移中的作用尚不清楚。在本研究中，我们研究了高度转移性 MDA-MB-231 人 BC 细胞中 hEag1 的功能表达及其对细胞迁移的影响。我们发现 hEag1mRNA 和蛋白在人浸润性导管癌组织和 BC 细胞系中均有表达。使用 hEag1 阻断剂 astemizole 或 siRNA 证实了 hEag1 通道在 MDA-MB-231 细胞中的功能活性。阻断或沉默 hEag1 会使膜电位去极化，并减少 Ca(2+)内流和 MDA-MB-231 细胞迁移，而不影响细胞增殖。最近的研究报道，Orai1 通道的 Ca(2+)内流是 MDA-MB-231 细胞迁移所必需的。下调 hEag1 或 Orai1 以相似的效率减少 Ca(2+)内流和细胞迁移。有趣的是，在共转染 sihEag1 和 siOrai1 的细胞中，观察到 Ca(2+)内流或细胞迁移没有叠加效应。最后，Orai1 和 hEag1 均在侵袭性乳腺腺癌组织和侵袭性转移性淋巴结样本（LNM(+)）中表达。总之，本研究首次证明 hEag1 通道通过控制 Orai1 通道的 Ca(2+)内流参与了 BC 细胞在血清诱导下的迁移。因此，hEag1 可能成为抑制 BC 细胞迁移和预防转移发展的潜在靶点。
