Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells
Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells
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DOI：
10.1152/ajpcell.00407.2010
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发表时间：
2011-05-01
影响因子：
5.5
通讯作者：
O'Connor, Kathleen L.
中科院分区：
文献类型：
--
作者：
Chen, Min;Sastry, Sarita K.;O'Connor, Kathleen L.
陈敏，陈志强，陈建平，等。Src激酶通路参与nfat5介导的高渗应激对结肠癌细胞S100A4的诱导。[J] .中国生物医学工程学报，2016,31(2):559 - 563。首次发表于2011年2月2日；doi: 10.1152 / ajpcell.00407.2010。-S100A4与许多类型的癌症以及一些非恶性疾病的进展有关。然而，它是如何被细胞内信号和/或转录水平调控的还没有广泛的研究。我们最近证明S100A4部分受到整合素α 6 β 4下游活化T细胞5 （NFAT5）核因子的调控。NFAT5是一种哺乳动物渗透调节因子。为了在更容易诱导的模型中研究NFAT5对S100A4的调控，我们对结肠癌细胞进行了高渗应激。我们发现S100A4在结肠癌细胞系的一个子集中被诱导，并且诱导S100A4的能力取决于S100A4的甲基化状态。通过S100A4荧光素酶报告基因检测，在S100A4的第一个内含子区鉴定了渗透胁迫响应元件。用小干扰RNA耗尽NFAT5可消除S100A4的诱导。此外，染色质免疫沉淀实验显示NFAT5被诱导结合到第一个内含子区域。Src激酶通路的抑制通过影响NFAT5的转激活和蛋白水平来降低S100A4的诱导。采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）法研究高渗应激条件下S100A4在结肠癌细胞中的诱导作用；结果表明，S100A4诱导有助于细胞存活。综上所述，本研究表明高渗应激通过NFAT5诱导S100A4， Src和染色质重塑参与其中。此外，S100A4的诱导有助于细胞存活。鉴于胃肠道周期性暴露于高渗应激，本研究可能揭示一种新的信号通路，可能有助于胃肠道癌症的进展。
Chen M, Sastry SK, O'Connor KL. Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells. Am J Physiol Cell Physiol 300: C1155-C1163, 2011. First published February 2, 2011; doi:10.1152/ajpcell.00407.2010.-S100A4 is associated with the progression of many types of cancers as well as several nonmalignant conditions. However, how it is regulated by intracellular signaling and/or at the transcriptional level has not been extensively studied. We recently demonstrated that S100A4 is partially regulated by nuclear factor in activated T cell 5 (NFAT5) downstream of integrin alpha 6 beta 4. NFAT5 is a mammalian osmotic regulator. To study the regulation of S100A4 by NFAT5 in a more readily inducible model, colon cancer cells were subjected to hyperosmotic stress. We found that S100A4 is induced in a subset of colon cancer cell lines, and the ability to induce S100A4 depends on the methylation status of S100A4. The osmotic stress response elements were identified in the first intron region of S100A4 by S100A4 luciferase reporter assays. Depletion of NFAT5 by small interfering RNA abolished S100A4 induction. Furthermore, chromatin immunoprecipitation assays showed that NFAT5 is induced to bind to the first intron region. Inhibition of Src kinase pathways reduced S100A4 induction by affecting NFAT5 transactivation and protein levels. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to study the function of S100A4 induction in colon cancer cells under the condition of hyperosmotic stress; the results suggest that S100A4 induction contributes to cell survival. In conclusion, this study demonstrates that hyperosmotic stress induces S100A4 through NFAT5, and Src and chromatin remodeling are involved. In addition, the induction of S100A4 contributes to cell survival. Given that the gastrointestinal tract is periodically exposed to hyperosmotic stress, this study may uncover a novel signaling pathway that could contribute to GI cancer progression.