Hoda Soleymani Abyaneh, Nidhi Gupta, Abdulraheem Alshareef, Keshav Gopal, Afsaneh Lavasanifar, Raymond Lai
{"title":"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","authors":"Hoda Soleymani Abyaneh, Nidhi Gupta, Abdulraheem Alshareef, Keshav Gopal, Afsaneh Lavasanifar, Raymond Lai","doi":"10.1007/s12307-018-0218-0","DOIUrl":null,"url":null,"abstract":"<p><p>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 CD44<sup>high</sup>/CD24<sup>low</sup> 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.</p>","PeriodicalId":9425,"journal":{"name":"Cancer Microenvironment","volume":"11 2-3","pages":"141-152"},"PeriodicalIF":0.0000,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12307-018-0218-0","citationCount":"24","resultStr":"{\"title\":\"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.\",\"authors\":\"Hoda Soleymani Abyaneh, Nidhi Gupta, Abdulraheem Alshareef, Keshav Gopal, Afsaneh Lavasanifar, Raymond Lai\",\"doi\":\"10.1007/s12307-018-0218-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 CD44<sup>high</sup>/CD24<sup>low</sup> 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.</p>\",\"PeriodicalId\":9425,\"journal\":{\"name\":\"Cancer Microenvironment\",\"volume\":\"11 2-3\",\"pages\":\"141-152\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2018-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1007/s12307-018-0218-0\",\"citationCount\":\"24\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Microenvironment\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s12307-018-0218-0\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2018/9/25 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Microenvironment","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s12307-018-0218-0","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2018/9/25 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
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.
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.