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由STAT3和p65调控的肿瘤微环境驱动网络对人HR+/HER2-乳腺癌中癌症干细胞的富集起负向调控作用。

A Tumor Microenvironment-Driven Network Regulated by STAT3 and p65 Negatively Controls the Enrichment of Cancer Stem Cells in Human HR+/HER2- Breast Cancer.

作者信息

Ben-Yaakov Hagar, Meshel Tsipi, Pasmanik-Chor Metsada, Körner Cindy, Ben-Baruch Adit

机构信息

The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.

Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.

出版信息

Cancers (Basel). 2023 Apr 12;15(8):2255. doi: 10.3390/cancers15082255.

DOI:10.3390/cancers15082255
PMID:37190183
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10137120/
Abstract

Hormone receptor-positive and HER2-negative (HR+/HER2-; luminal A) tumors are prevalent in breast cancer. Our past studies demonstrated that "TME Stimulation" (estrogen + TNFα + EGF, representing three arms of the tumor microenvironment, TME) has enriched metastasis-forming cancer stem cells (CSCs) in HR+/HER2- human breast cancer cells. Here, following information obtained by RNAseq analyses of TME-stimulated CSCs and Non-CSCs, we found that TME Stimulation has induced the activation of S727-STAT3, Y705-STAT3, STAT1 and p65. Upon TME Stimulation, stattic (STAT3 inhibitor) usage demonstrated that Y705-STAT3 activation negatively controlled CSC enrichment and epithelial-to-mesenchymal transition (EMT) traits, while inducing CXCL8 (IL-8) and PD-L1 expression. However, STAT3 knock-down (siSTAT3) had no effect on these functions; in terms of CSC enrichment, p65 had down-regulatory roles that compensated for the loss of an entire STAT3 protein. Y705-STAT3 and p65 acted additively in reducing CSC enrichment, and Y705A-STAT3 variant + sip65 has enriched chemo-resistant CSCs. Clinical data analyses revealed an inverse correlation between Y705-STAT3 + p65 phosphorylation and CSC signature in luminal A patients, and connection to improved disease course. Overall, we find regulatory roles for Y705-STAT3 and p65 in TME-stimulated HR+/HER2- tumors, with the ability to limit CSC enrichment. These findings raise concerns about using inhibitors of STAT3 and p65 as therapeutic strategies in the clinic.

摘要

激素受体阳性且人表皮生长因子受体2阴性（HR+/HER2-；管腔A型）肿瘤在乳腺癌中很常见。我们过去的研究表明，“肿瘤微环境刺激”（雌激素+肿瘤坏死因子α+表皮生长因子，代表肿瘤微环境的三个方面，即TME）使HR+/HER2-人乳腺癌细胞中形成转移的癌症干细胞（CSCs）增多。在此，根据对肿瘤微环境刺激的癌症干细胞和非癌症干细胞进行RNA测序分析所获得的信息，我们发现肿瘤微环境刺激已诱导S727-信号转导和转录激活因子3（STAT3）、Y705-STAT3、信号转导和转录激活因子1（STAT1）以及p65激活。在肿瘤微环境刺激后，使用STAT3抑制剂（Stattic）表明，Y705-STAT3激活对癌症干细胞富集和上皮-间质转化（EMT）特征起负调控作用，同时诱导CXC趋化因子配体8（CXCL8，即白细胞介素8）和程序性死亡配体1（PD-L1）表达。然而，敲低STAT3（siSTAT3）对这些功能没有影响；就癌症干细胞富集而言，p65具有下调作用，可弥补整个STAT3蛋白缺失的影响。Y705-STAT3和p65在减少癌症干细胞富集方面具有累加作用，而Y705A-STAT3变体+sip65使化疗耐药性癌症干细胞增多。临床数据分析显示，管腔A型患者中Y705-STAT3 + p65磷酸化与癌症干细胞特征呈负相关，并与疾病进程改善有关。总体而言，我们发现Y705-STAT3和p65在肿瘤微环境刺激的HR+/HER2-肿瘤中具有调控作用，能够限制癌症干细胞富集。这些发现引发了对在临床中使用STAT3和p65抑制剂作为治疗策略的担忧。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/16c1eaa64e99/cancers-15-02255-g014.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/e1875a98fa7a/cancers-15-02255-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/7ba95599b7f1/cancers-15-02255-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/327e610e31d2/cancers-15-02255-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/3a020c580d8b/cancers-15-02255-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e587/10137120/1b8c66a2bfb9/cancers-15-02255-g012.jpg
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2
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3
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4
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