Lange L, Hüsing T, Rauschner M, Riemann Anne, Thews O
Julius-Bernstein-Institute of Physiology, University of Halle, Halle (Saale), Germany.
Adv Exp Med Biol. 2021;1269:145-149. doi: 10.1007/978-3-030-48238-1_23.
The metabolic microenvironment in tumors is characterized by hypoxia and acidosis. Extracellular pH sometimes decreases to even below 6.0. Previous experiments showed that tissue pH has an impact on tumor cell proliferation and apoptosis. However, the mechanism of how cell cycle progression is affected by decreased pH is not fully understood yet. One possible mechanism includes changes in the expression of miRNAs. The aim of this study was to analyze the impact of pH-regulated miRNAs (miR-183 and miR-215) on proliferation, apoptosis, and necrosis of tumor cells. Therefore, AT1 prostate and Walker-256 mammary carcinoma cells were transfected with the miRNAs or with the respective antagomirs and incubated at pH 7.4 and 6.6 for 24 h. AT1 cells underwent a G0/G1 cell cycle arrest under acidic conditions and showed a marked reduction of the number of actively DNA-synthesizing cells. In Walker-256 cells, acidosis induced a reduction of apoptosis and additionally a significant increase in necrotic cell death. Transfection of tumor cells with miR-183 or miR-215, which were significantly downregulated under acidic conditions, had no impact on cell death of AT1 or Walker-256 cells. Overexpression of miR-183, which is also downregulated by acidosis, intensified G0/G1 cell cycle arrest in AT1 cells. Previous studies revealed that hypoxia-related tumor acidosis affects the expression of different small noncoding RNAs. However, not all of these acidosis-regulated miRNAs seem to have an impact on proliferation, apoptosis, and necrosis of tumor cells. While miR-215 had no influence, miR-183 seems to be an interesting candidate that could amplify the impact of extracellular acidosis on malignant behavior of tumor cells.
肿瘤中的代谢微环境以缺氧和酸中毒为特征。细胞外pH有时会降至甚至低于6.0。先前的实验表明，组织pH对肿瘤细胞的增殖和凋亡有影响。然而，pH降低如何影响细胞周期进程的机制尚未完全阐明。一种可能的机制包括miRNA表达的变化。本研究的目的是分析pH调节的miRNA（miR-183和miR-215）对肿瘤细胞增殖、凋亡和坏死的影响。因此，将miRNA或各自的拮抗剂转染到AT1前列腺癌细胞和Walker-256乳腺癌细胞中，并在pH 7.4和6.6下孵育24小时。AT1细胞在酸性条件下经历G0/G1细胞周期阻滞，并显示出活跃进行DNA合成的细胞数量显著减少。在Walker-256细胞中，酸中毒导致凋亡减少，此外坏死性细胞死亡显著增加。用在酸性条件下显著下调的miR-183或miR-215转染肿瘤细胞，对AT1或Walker-256细胞的细胞死亡没有影响。同样在酸中毒时下调的miR-183的过表达加剧了AT1细胞中的G0/G1细胞周期阻滞。先前的研究表明，缺氧相关的肿瘤酸中毒会影响不同小非编码RNA的表达。然而，并非所有这些酸中毒调节的miRNA似乎都对肿瘤细胞的增殖、凋亡和坏死有影响。虽然miR-215没有影响，但miR-183似乎是一个有趣的候选者，它可能会放大细胞外酸中毒对肿瘤细胞恶性行为的影响。
