ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4.
ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4.
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ESE3/EHF 是罗格列酮的一个有前景的靶标，通过下调 CXCR4 抑制胰腺癌干细胞
DOI：
10.1136/gutjnl-2020-321952
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发表时间：
2022-03
期刊：
影响因子：
24.5
通讯作者：
Hao, Jihui
中科院分区：
文献类型：
--
作者：
Zhou, Tianxing;Liu, Jing;Xie, Yongjie;Yuan, Shuai;Guo, Yu;Bai, Weiwei;Zhao, Kaili;Jiang, Wenna;Wang, Hongwei;Wang, Haotian;Zhao, Tiansuo;Huang, Chongbiao;Gao, Song;Wang, Xiuchao;Yang, Shengyu;Hao, Jihui
背景与目的肿瘤干细胞（cancer stem cells，CSCs）与其小生境之间的相互作用是维持CSCs干细胞样表型所必需的。在这里，我们确定E26转化特异性同源因子（EHF）是降低胰腺癌（PC）细胞对CSC的小生境刺激敏感性的关键分子。我们还探索了恢复EHF表达的治疗策略。我们使用LSL-KrasG 12 D/+小鼠、LSL-Trp 53 R172 H/+和Pdx 1-Cre（KPC）小鼠模型和来自PC患者的样品。本研究进行了免疫染色、流式细胞术、球体形成试验、锚定非依赖性生长试验、体内致瘤性、逆转录PCR、染色质免疫沉淀（ChIP）和荧光素酶分析。结果来源于胰腺星状细胞的CXCL 12介导了PC细胞与PSCs之间的相互作用，促进了PC的干性。肿瘤性EHF通过降低PC对CXCL 12刺激的敏感性和抑制PC与CSC支持性小生境之间的串扰来抑制CSC的干性。在机制上，EHF抑制了CXCL 12受体CXCR 4的转录。EHF通过抑制Sox 9、Sox 2、Oct 4和Nanog基因的转录，发挥细胞自主性的作用。罗格列酮通过上调EHF抑制PC的干性，抑制PC与PSC之间的串扰。临床前KPC小鼠队列研究表明，罗格列酮使PDAC对吉西他滨治疗敏感。结论EHF通过负性调节肿瘤细胞CXCR 4，降低PC对PSC来源的CSC支持小生境刺激的敏感性。罗格列酮可通过上调EHF靶向PC干细胞以及CSC与其生态位之间的串扰。
Background and aims The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs’ niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF. Design We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study. Results CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy. Conclusions EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.
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DOI：
10.1186/s13046-017-0557-6
发表时间：
2017-07-03
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Fujita M;Hasegawa A;Yamamori M;Okamura N
通讯作者：
Okamura N
影响因子：
5.8
作者：
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Hollingsworth, Michael A.
影响因子：
29.4
作者：
Crawford, Howard C.;di Magliano, Marina Pasca;Banerjee, Sulagna
通讯作者：
Banerjee, Sulagna
影响因子：
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作者：
Albino D;Civenni G;Rossi S;Mitra A;Catapano CV;Carbone GM
通讯作者：
Carbone GM
影响因子：
3.4
作者：
Li, Yue;Zhang, Da-Wei;Cao, Liang-Qi
通讯作者：
Cao, Liang-Qi