The epithelial polarity axis controls the resting membrane potential and Cl- co-transport in breast glandular structures.
The epithelial polarity axis controls the resting membrane potential and Cl- co-transport in breast glandular structures.
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DOI：
10.1242/jcs.260924
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发表时间：
2024-03-01
影响因子：
4
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中科院分区：
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膜电位（MP）通过指导分子转运和基因表达来控制细胞稳态。MP如何影响上皮细胞分化尚不清楚。考虑到组织结构也控制着体内平衡，我们在HMT-3522乳腺癌进展的三维培养中研究了基顶极性和静息MP之间的关系。微电极技术测量了MP和输入电阻，发现MP由间隙连接细胞间通讯（GJIC）提高，GJIC指导紧密连接介导的顶端极性，而Na+/K+/2Cl−（NKCC，由SLC12A1和SLC12A2编码）共转运蛋白降低，NKCC在显示基极性的多细胞结构中活跃。在肿瘤对应物中，MP降低。癌细胞显示GJIC减少，对速尿没有反应，这意味着NKCC活性的丧失。诱导癌细胞分化为基本极化的多细胞结构恢复了广泛的GJIC和NKCC反应，但这些结构显示出最低的MP。在活跃的Cl−运输下，非肿瘤上皮中缺乏根尖极性（癌症发生所必需的）也与最低的MP有关。我们认为，乳腺上皮顶端极性的丧失在一定程度上通过降低MP来破坏细胞稳态的稳定。摘要：上皮极性通过对膜电位的影响在控制细胞稳态中起着核心作用。
The membrane potential (MP) controls cell homeostasis by directing molecule transport and gene expression. How the MP is set upon epithelial differentiation is unknown. Given that tissue architecture also controls homeostasis, we investigated the relationship between basoapical polarity and resting MP in three-dimensional culture of the HMT-3522 breast cancer progression. A microelectrode technique to measure MP and input resistance reveals that the MP is raised by gap junction intercellular communication (GJIC), which directs tight-junction mediated apical polarity, and is decreased by the Na+/K+/2Cl− (NKCC, encoded by SLC12A1 and SLC12A2) co-transporter, active in multicellular structures displaying basal polarity. In the tumor counterpart, the MP is reduced. Cancer cells display diminished GJIC and do not respond to furosemide, implying loss of NKCC activity. Induced differentiation of cancer cells into basally polarized multicellular structures restores widespread GJIC and NKCC responses, but these structures display the lowest MP. The absence of apical polarity, necessary for cancer onset, in the non-neoplastic epithelium is also associated with the lowest MP under active Cl− transport. We propose that the loss of apical polarity in the breast epithelium destabilizes cellular homeostasis in part by lowering the MP. Summary: There is a central role for epithelial polarity in controlling cell homeostasis via an impact on the membrane potential.
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