Acidic microenvironment induction of interleukin-8 expression and matrix metalloproteinase-2/-9 activation via acid-sensing ion channel 1 promotes breast cancer cell progression
Acidic microenvironment induction of interleukin-8 expression and matrix metalloproteinase-2/-9 activation via acid-sensing ion channel 1 promotes breast cancer cell progression
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DOI：
10.3892/or.2020.7907
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发表时间：
2021-03-01
期刊：
影响因子：
4.2
通讯作者：
Muragaki, Yasuteru
中科院分区：
文献类型：
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作者：
Nakanishi, Masako;Korechika, Ayaka;Muragaki, Yasuteru
与周围正常组织相比，癌症微环境表现出局部酸中毒。许多研究表明，酸中毒可加速肿瘤的侵袭和转移，但其分子机制尚不清楚。在本研究中，我们专注于酸诱导的功能变化，通过酸受体在乳腺癌细胞。酸处理诱导MDA-MB-231细胞表达白细胞介素（IL）-8，并促进细胞迁移和侵袭。酸性微环境升高了基质金属蛋白酶（MMP）-2和MMP-9的活性，加入IL-8也有类似的效果。然而，抑制IL-8抑制酸诱导的MDA-MB-231细胞的迁移和侵袭。MDA-MB-231细胞表达多种酸受体，包括离子通道和G蛋白偶联受体。有趣的是，酸刺激增加了酸敏感离子通道1（ASIC 1）的表达，而ASIC 1敲低则显著降低了酸诱导的IL-8。此外，磷酸化的核因子（NF）-κ B B诱导的酸处理，抑制NF-κ B活化减少酸诱导的IL-8的表达。这些结果表明，酸性微环境诱导IL-8促进乳腺癌的发展，ASIC 1可能是乳腺癌转移的新治疗靶点。
The cancer microenvironment exhibits local acidosis compared with the surrounding normal tissue. Many reports have shown that acidosis accelerates the invasiveness and metastasis of cancer, yet the underlying molecular mechanisms remain unclear. In the present study, we focused on acid-induced functional changes through acid receptors in breast cancer cells. Acidic treatment induced interleukin (IL)-8 expression in MDA-MB-231 cells and promoted cell migration and invasion. The acidic microenvironment elevated matrix metalloproteinase (MMP)-2 and MMP-9 activity, and addition of IL-8 had similar effects. However, inhibition of IL-8 suppressed the acid-induced migration and invasion of MDA-MB-231 cells. MDA-MB-231 cells express various acid receptors including ion channels and G protein-coupled receptors. Interestingly, acidic stimulation increased the expression of acid-sensing ion channel 1 (ASIC1), and acid-induced IL-8 was significantly decreased by ASIC1 knockdown. Moreover, phosphorylation of nuclear factor (NF)-kappa B was induced by acidic treatment, and inhibition of NF-kappa B activation reduced acid-induced IL-8 expression. These results suggest that IL-8 induction by an acidic microenvironment promotes breast cancer development and that ASIC1 might be a novel therapeutic target for breast cancer metastasis.