Regulation of breast tumorigenesis through acid sensors.
Regulation of breast tumorigenesis through acid sensors.
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作者：
Gupta SC;Singh R;Asters M;Liu J;Zhang X;Pabbidi MR;Watabe K;Mo YY
微环境中的低细胞外pH已被证明促进肿瘤生长和转移，然而，其潜在机制知之甚少。特别是，很少有人知道肿瘤细胞如何感知酸性信号，以激活酸中毒介导的信号。在这项研究中，我们表明，乳腺癌细胞表达酸敏感离子通道1（ASIC 1），质子门控阳离子通道主要在神经系统中表达。RNA干扰、基因敲除和拯救实验表明，ASIC 1在酸中毒诱导的反应性氧化物质和NF-κB激活中发挥关键作用，这是肿瘤发生的两个关键事件。从机制上讲，ASIC 1是通过钙内流进行酸中毒介导的信号传导所必需的。我们发现，作为一种细胞质膜蛋白，ASIC 1也与线粒体，这表明ASIC 1可能调节线粒体钙内流。重要的是，对癌症基因组图谱乳腺浸润性癌数据集的询问表明，ASIC 1单独或与其他4种ASIC基因组合的改变与患者生存率差显著相关。此外，ASIC 1抑制剂导致肿瘤生长和肿瘤负荷的显著降低。总之，这些结果表明，ASIC 1有助于乳腺癌的发病机制，在响应酸性肿瘤微环境，ASIC 1可以作为乳腺癌的预后标志物和治疗靶点。
The low extracellular pH in the microenvironment has been shown to promote tumor growth and metastasis, however, the underlying mechanism is poorly understood. Particularly, little is known how the tumor cell senses the acidic signal to activate the acidosis-mediated signaling. In this study, we show that breast cancer cells express acid-sensing ion channel 1 (ASIC1), a proton-gated cation channel primarily expressed in the nervous system. RNA interference, knockout and rescue experiments demonstrate a critical role for ASIC1 in acidosis-induced reactive oxidative species and NF-κB activation, two key events for tumorigenesis. Mechanistically, ASIC1 is required for acidosis-mediated signaling through calcium influx. We show that as a cytoplasmic membrane protein, ASIC1 is also associated with mitochondria, suggesting that ASIC1 may regulate mitochondrial calcium influx. Importantly, interrogation of the Cancer Genome Atlas breast invasive carcinoma dataset indicates that alterations of ASIC1 alone or combined with other 4 ASIC genes are significantly correlated with poor patient survival. Furthermore, ASIC1 inhibitors cause a significant reduction of tumor growth and tumor load. Together, these results suggest that ASIC1 contributes to breast cancer pathogenesis in response to acidic tumor microenvironments, and ASIC1 may serve as a prognostic marker and a therapeutic target for breast cancer.
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影响因子：
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影响因子：
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作者：
Gupta SC;Singh R;Pochampally R;Watabe K;Mo YY
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