缺氧通过上调和激活三阴性乳腺癌细胞系MDA-MB-231的信号转导和转录激活因子3 (STAT3)诱导癌症茎样表型的获得

Q2 Medicine
Cancer Microenvironment Pub Date : 2018-12-01 Epub Date: 2018-09-25 DOI:10.1007/s12307-018-0218-0
Hoda Soleymani Abyaneh, Nidhi Gupta, Abdulraheem Alshareef, Keshav Gopal, Afsaneh Lavasanifar, Raymond Lai
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引用次数: 24

摘要

在各种实验模型中发现缺氧可以诱导肿瘤干性,这与癌细胞可塑性的概念基础是一致的。在这里,我们旨在深入了解缺氧诱导三阴性乳腺癌(TNBC)癌细胞可塑性的分子基础。为了实现这一目标,我们采用了我们之前发表的TNBC体外模型,其中一小部分干细胞样细胞可以根据它们对Sox2报告基因的反应性与大细胞群区分开来。在MDA-MB-231 TNBC细胞系中,我们观察到缺氧显著增加了荧光素酶和绿色荧光蛋白(GFP)的表达,这是Sox2报告基因的读数。在低氧刺激下,大量报告细胞无反应(RU)获得了干细胞样特征,cd44高/ cd24低细胞比例、集落形成和对顺铂的耐药性显著增加证明了这一点。与这些表型变化相关的是,暴露于缺氧的RU细胞表现出STAT3活性/磷酸化形式(pSTAT3)的大幅上调。缺氧诱导的STAT3激活与STAT3转录活性的增加相关,STAT3- dna结合的增加和基因表达谱的改变证明了这一点。这种缺氧诱导的STAT3激活具有重要的生物学意义,因为RU细胞中STAT3的siRNA敲低显著减弱了缺氧诱导的Sox2活性获得和茎样表型特征。总之,我们的数据已经提供了概念证明,STAT3是促进缺氧诱导的TNBC癌症干细胞获得的关键介质。在TNBC中靶向STAT3可能有助于克服化疗耐药和降低疾病复发的风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hypoxia Induces the Acquisition of Cancer Stem-like Phenotype Via Upregulation and Activation of Signal Transducer and Activator of Transcription-3 (STAT3) in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Hypoxia Induces the Acquisition of Cancer Stem-like Phenotype Via Upregulation and Activation of Signal Transducer and Activator of Transcription-3 (STAT3) in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Hypoxia Induces the Acquisition of Cancer Stem-like Phenotype Via Upregulation and Activation of Signal Transducer and Activator of Transcription-3 (STAT3) in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Hypoxia Induces the Acquisition of Cancer Stem-like Phenotype Via Upregulation and Activation of Signal Transducer and Activator of Transcription-3 (STAT3) in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

The finding that hypoxia can induce cancer stemness in various experimental models is in agreement with the conceptual basis of cancer cell plasticity. Here, we aimed to gain insights into the molecular basis of hypoxia-induced cancer cell plasticity in triple negative breast cancer (TNBC). To achieve this goal, we employed our previously published in-vitro model of TNBC, in which a small subset of stem-like cells can be distinguished from the bulk cell population based on their responsiveness to a Sox2 reporter. In MDA-MB-231, a TNBC cell line, we observed that hypoxia significantly increased the expression of luciferase and green fluorescence protein (GFP), the readouts of the Sox2 reporter. Upon hypoxic challenge, the bulk, reporter unresponsive (RU) cells acquired stem-like features, as evidenced by the significant increases in the proportion of CD44high/CD24low cells, colony formation and resistance to cisplatin. Correlating with these phenotypic changes, RU cells exposed to hypoxia exhibited a substantial upregulation of the active/phosphorylated form of STAT3 (pSTAT3). This hypoxia-induced activation of STAT3 correlated with increased STAT3 transcriptional activity, as evidenced by increased STAT3-DNA binding and an altered gene expression profile. This hypoxia-induced STAT3 activation is biologically significant, since siRNA knockdown of STAT3 in RU cells significantly attenuated the hypoxia-induced acquisition of Sox2 activity and stem-like phenotypic features. In conclusion, our data have provided the proof-of-concept that STAT3 is a critical mediator in promoting the hypoxia-induced acquisition of cancer stemness in TNBC. Targeting STAT3 in TNBC may be useful in overcoming chemoresistance and decreasing the risk of disease relapse.

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来源期刊
Cancer Microenvironment
Cancer Microenvironment Medicine-Oncology
CiteScore
4.90
自引率
0.00%
发文量
0
期刊介绍: Cancer Microenvironment is the official journal of the International Cancer Microenvironment Society (ICMS). It publishes original studies in all aspects of basic, clinical and translational research devoted to the study of cancer microenvironment. It also features reports on clinical trials. Coverage in Cancer Microenvironment includes: regulation of gene expression in the cancer microenvironment; innate and adaptive immunity in the cancer microenvironment, inflammation and cancer; tumor-associated stroma and extracellular matrix, tumor-endothelium interactions (angiogenesis, extravasation), cancer stem cells, the metastatic niche, targeting the tumor microenvironment: preclinical and clinical trials.
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