Julius-Bernstein-Institute of Physiology, University of Halle, Halle, Germany.
Adv Exp Med Biol. 2024;1463:285-291. doi: 10.1007/978-3-031-67458-7_47.
Tumours often exhibit pronounced hypoxia and hereby extracellular acidosis due to intensified glycolysis. Since metabolic parameters can modulate gene expression, the aim of the study was to analyse changes in gene expression patterns induced by acute (24 h) acidosis or hypoxia and also in tumour cells adapted to long-term acidosis (5 weeks). Three tumour cell lines (AT1 prostate carcinoma, MCF-7, and MDA-MB-231 breast carcinoma) were exposed to acidosis (pH 6.6) or hypoxia (pO 1.5 mmHg) for 24 h. For long-term acidosis, AT1 tumour cells were continuously cultured at pH 6.6 for 5 weeks. Gene expression was examined by total RNA-sequencing and the functional significance was assessed by gene set enrichment analysis using the Gene Ontology database. Under short-term acidosis (24 h), AT1 and MCF-7 cells showed comparable changes. 714 genes were acidosis-dependently regulated in AT1 cells (275 up, 439 down), and 221 genes in MCF-7 cells (95 up, 126 down). MDA-MB-231 cells almost did not respond to low pH (13 regulated genes). Hypoxia affected MCF-7 cells the most (1498 regulated genes), whereas fewer genes were regulated in AT1 and MDA-MB-231 cells. Concerning the function of the regulated genes by short-term acidosis, RNA processing, cell cycle regulation, DNA synthesis, and mitochondrial function were negatively affected. Chronic acidosis showed a different picture. In AT1 cells, 1160 genes were differentially expressed (638 up, 522 down) when cells exposed to low pH for 5 weeks. The putatively acidosis-induced changes in functions included tissue structural development, RNA processing, and mitochondrial activity. This study shows that both acute and chronic acidosis of tumour cells lead to altered gene expression and thus affect cell function. Long-term acidosis leads to fundamentally different changes, indicating an adaptation process of the tumour cells.
肿瘤常因糖酵解增强而表现出明显的缺氧和细胞外酸中毒。由于代谢参数可以调节基因表达，因此本研究的目的是分析急性（24 小时）酸中毒或缺氧以及长期酸中毒（5 周）适应的肿瘤细胞诱导的基因表达模式的变化。三种肿瘤细胞系（前列腺癌 AT1、MCF-7 和 MDA-MB-231 乳腺癌）分别暴露于酸中毒（pH 6.6）或缺氧（pO 1.5 mmHg）24 小时。为了长期酸中毒，AT1 肿瘤细胞连续在 pH 6.6 下培养 5 周。通过总 RNA 测序检查基因表达，并使用基因本体数据库通过基因集富集分析评估功能意义。在短期酸中毒（24 小时）下，AT1 和 MCF-7 细胞表现出相似的变化。在 AT1 细胞中，有 714 个基因受酸中毒调节（275 个上调，439 个下调），在 MCF-7 细胞中，有 221 个基因受酸中毒调节（95 个上调，126 个下调）。MDA-MB-231 细胞对低 pH 值几乎没有反应（13 个调节基因）。缺氧对 MCF-7 细胞的影响最大（1498 个调节基因），而 AT1 和 MDA-MB-231 细胞中调节的基因较少。关于短期酸中毒调节基因的功能，RNA 加工、细胞周期调节、DNA 合成和线粒体功能受到负面影响。慢性酸中毒呈现出不同的图景。在 AT1 细胞中，当细胞暴露于低 pH 值 5 周时，有 1160 个基因差异表达（638 个上调，522 个下调）。功能上推测的酸中毒诱导变化包括组织结构发育、RNA 加工和线粒体活性。本研究表明，肿瘤细胞的急性和慢性酸中毒都会导致基因表达的改变，从而影响细胞功能。长期酸中毒会导致根本不同的变化，表明肿瘤细胞的适应过程。
