HIFα independent mechanisms in renal carcinoma cells modulate divergent outcomes in fibronectin assembly mediated by hypoxia and CoCl(2).
HIFα independent mechanisms in renal carcinoma cells modulate divergent outcomes in fibronectin assembly mediated by hypoxia and CoCl(2).
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DOI：
10.1038/s41598-020-75756-5
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发表时间：
2020-10-29
影响因子：
4.6
通讯作者：
Varadaraj A
中科院分区：
文献类型：
--
作者：
Magdaleno C;Dixon L;Rajasekaran N;Varadaraj A
纤连蛋白（FN）是一种核心基质蛋白，其组装形成动态细胞支架，在致癌转化过程中经常受到干扰。以大多数实体瘤微环境中的低氧浓度为特征的肿瘤缺氧已显示加速成纤维细胞和癌症相关成纤维细胞（产生大量FN蛋白的细胞类型）中的FN组装。然而，缺氧期间上皮癌细胞中FN基质的调节仍然不太清楚。在这项研究中，我们调查的组装FN矩阵缺氧过程中在肾癌上皮细胞，细胞的起源肾细胞癌（RCC）。我们发现，缺氧（1%O2），特别是增加矩阵分解，并增加肾癌细胞的迁移倾向。然而，使用低氧模拟物的HIFα稳定化不能概括低氧对FN基质重组或细胞迁移的影响。使用敲除和基于通道的方法相结合，我们的工作表征了介导基质上这两种不同变化的信号传导事件，并探讨了其对趋化细胞迁移的功能意义。我们的研究系统地重新审视了缺氧模拟物作为缺氧实验替代品的作用，并提供了在肾癌背景下HIFα稳定性和FN基质的新发现。
Fibronectin (FN) is a core matrix protein that assembles to form a dynamic cellular scaffold, frequently perturbed during oncogenic transformation. Tumor hypoxia, characterized by low oxygen concentrations in the microenvironment of most solid tumors has been shown to accelerate FN assembly in fibroblasts and cancer-associated fibroblasts, cell types that produce abundant amounts of FN protein. Nevertheless, FN matrix regulation in epithelial cancer cells during hypoxia remains less well defined. In this study we investigate the assembly of the FN matrix during hypoxia in renal cancer epithelial cells, the cells of origin of renal cell carcinoma (RCC). We show that hypoxia (1% O2) specifically increases matrix disassembly and increases migratory propensity in renal cancer cells. However, HIFα stabilization using hypoxia mimetics, does not recapitulate the effect of hypoxia on FN matrix reorganization or cell migration. Using a combination of knockdown and inhibitor-based approaches, our work characterizes the signaling events that mediate these two disparate changes on the matrix and explores its functional significance on chemotactic cell migration. Our study systematically reexamines the role of hypoxia mimetics as experimental substitutes for hypoxia and provides new findings on HIFα stabilization and the FN matrix in the context of renal cancer.
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DOI：
10.1083/jcb.201704053
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Erdogan B;Ao M;White LM;Means AL;Brewer BM;Yang L;Washington MK;Shi C;Franco OE;Weaver AM;Hayward SW;Li D;Webb DJ
通讯作者：
Webb DJ
影响因子：
3.4
作者：
Lemmon, Christopher A.;Chen, Christopher S.;Romer, Lewis H.
通讯作者：
Romer, Lewis H.
影响因子：
4
作者：
Rana, Manish K.;Srivastava, Jyoti;Barber, Diane L.
通讯作者：
Barber, Diane L.
DOI：
10.1074/mcp.m111.014647
发表时间：
2012-04
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Naba A;Clauser KR;Hoersch S;Liu H;Carr SA;Hynes RO
通讯作者：
Hynes RO
影响因子：
2.6
作者：
McKeown, S. R.
通讯作者：
McKeown, S. R.