Acid-Base Homeostasis and Implications to the Phenotypic Behaviors of Cancer
Acid-Base Homeostasis and Implications to the Phenotypic Behaviors of Cancer
复制标题
酸碱稳态及其对癌症表型行为的影响
DOI：
10.1101/2022.03.04.482927
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发表时间：
2022
影响因子：
9.5
通讯作者：
Xu, Ying
中科院分区：
文献类型：
--
作者：
Zhou, Yi;Chang, Wennan;Lu, Xiaoyu;Wang, Jin;Zhang, Chi;Xu, Ying
酸碱平衡是活细胞的基本特性，它在人类细胞中的持续破坏可导致广泛的疾病。在本研究中，我们对癌症基因组图谱（TCGA）数据库中9种癌症类型的4750个人体组织样本的转录组学数据进行了计算建模分析。基于我们之前的研究，我们定量地估计了通过细胞内的fenton反应产生OH−的平均速率，该反应持续地破坏细胞内pH （pHi）的稳态。我们的预测表明，43种重编程代谢（RMs）的全部或至少一部分被诱导以相当的芬顿反应速率产生净质子（H+），以保持pHistable。我们随后发现，许多众所周知的癌症表型，包括增加的生长速度、转移率和局部免疫细胞组成，可以用芬顿反应水平和诱导的RMs来自然地解释。这项研究强烈表明，有可能有一个统一的框架来研究癌症诱导压力源、适应性代谢重编程和癌症行为。此外，强有力的证据表明，Na+/H+交换剂与乳酸出口和碳酸酐酶一起负责癌症细胞内碱化和细胞外酸化的流行观点可能是不合理的。
Acid–base homeostasisis a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH−by cytosolicFenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHistable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptivemetabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.