Phenotypic transition of tumor cells between epithelial- and mesenchymal-like state during adaptation to acidosis
Phenotypic transition of tumor cells between epithelial- and mesenchymal-like state during adaptation to acidosis
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适应酸中毒过程中肿瘤细胞在上皮样和间质样状态之间的表型转变
DOI：
10.1080/15384101.2019.1635868
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发表时间：
2019-06
期刊：
影响因子：
4.3
通讯作者：
Li Jinlong
中科院分区：
文献类型：
--
作者：
Zhang Yongjun;Xu Lili;Wang Ping;Jian Huanzhang;Shi Xianghua;Jia Min;Mo Lijun;Hu Zhiming;Li Hongwei;Li Jinlong
酸性微环境是实体瘤发生恶性转化的重要特征。低的细胞外pH可以促进上皮-间质转化（EMT），从而使肿瘤细胞具有更高的侵袭能力。然而，EMT与长期酸性条件下肿瘤细胞增殖的关系尚不完全清楚。在这里，我们发现肿瘤细胞在适应酸中毒的过程中经历了从EMT到间充质上皮转化（MET）的表型转变，并且与细胞增殖状态密切相关。在酸性胁迫的早期，肿瘤细胞进入非循环的静息状态，呈间充质表型，高水平表达干性基因。然而，经过长期酸培养（2个月），酸适应细胞恢复增殖，但失去间充质表型。此外，我们的研究结果表明，酸适应细胞与非酸细胞具有不同的增殖机制，因为G1-S转录因子E2F1蛋白在适应细胞中没有恢复。同时，迷你染色体维持7 （MCM7）调节EMT到MET表型的转变，并且是适应细胞在酸性条件下增殖所必需的。MCM7敲低可促进间充质表型，抑制酸适应细胞的增殖。而MCM7过表达抑制酸诱导的EMT，支持酸性条件下肿瘤细胞的增殖。因此，我们的研究提供了证据，证明肿瘤细胞表现出表型可塑性，使它们能够在酸胁迫下生存。
ABSTRACT Acidic microenvironment is an important feature of solid tumors that contributes to malignant transformation. Low extracellular pH could promote epithelial-mesenchymal transition (EMT) thereby endowing tumor cells with higher invasive capability. However, the relation between EMT and tumor cell proliferation under long-term acidic condition is still not fully understood. Here, we show that tumor cells have undergone a phenotypic transition from EMT to mesenchymal-epithelial transition (MET) during adaptation to acidosis, and is closely related with cell proliferative state. Under early stage of acidic stress, tumor cells entered a non-cycling quiescent state with mesenchymal phenotype and expressed high level of stemness genes. Whereas, after long-term acid culture (2 months), acid-adapted cells resumed proliferating but lost mesenchymal phenotype. Further, our results show that the acid-adapted cells have distinct proliferative mechanism from non-acid cells, as the G1-S transcriptional factor E2F1 protein was not recovered in the adapted cells. Meanwhile, mini-chromosome maintenance 7 (MCM7) is shown to regulate the EMT to MET phenotypic transition, and is required for proliferation of the adapted cells under acidic condition. MCM7 Knockdown promoted mesenchymal phenotype and inhibited proliferation of the acid-adapted cells. While, MCM7 overexpression inhibited acid-induced EMT and supported tumor cell proliferation under acidic condition. Thus, our study provides evidence that tumor cells display phenotypic plasticity that allows them to survive acid stress.
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DOI：
10.1155/2014/574850
发表时间：
2014
期刊：
Molecular biology international
影响因子：
--
作者：
Das M;Singh S;Pradhan S;Narayan G
通讯作者：
Narayan G
影响因子：
6.6
作者：
Suarez-Carmona M;Lesage J;Cataldo D;Gilles C
通讯作者：
Gilles C
影响因子：
3.8
作者：
Li J;Zhou BP
通讯作者：
Zhou BP
DOI：
10.1016/s0360-3016(00)01590-x
发表时间：
2001-04
期刊：
International journal of radiation oncology, biology, physics
影响因子：
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作者：
T. Ohtsubo;H. Igawa;T. Saito;H. Matsumoto;H. Park;C. Song;E. Kano;H. Saito
通讯作者：
T. Ohtsubo;H. Igawa;T. Saito;H. Matsumoto;H. Park;C. Song;E. Kano;H. Saito
DOI：
--
发表时间：
2010
期刊：
Acta Universitatis Medicinalis Nanjing
影响因子：
--
作者：
H. Nanjing
通讯作者：
H. Nanjing