Guo Liantao, Rao Yan, Song Yawen, Hu Jiawei, Luo Zixuan, Sun Shengrong, Chen Chuang, Kong Deguang
Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Animal Biosafety Level III Laboratory at the Center for Animal Experiment, Wuhan University School of Medicine, Wuhan, Hubei, China.
Oncogene. 2025 Jul 26. doi: 10.1038/s41388-025-03499-6.
Epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSCs) are pivotal in breast cancer mechanism research. It was demonstrated that Sine oculis homeobox homolog 1 (SIX1) orchestrates breast cancer EMT and BCSCs, concurrently activating the Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Yet, the mechanism by which SIX1 modulates STAT3 and its potential to regulate EMT and BCSCs through STAT3 signaling remain unexplored. Here, cellular, animal, organoid models, and integrated single-cell transcriptomic and ST-seq of human breast cancer specimens were conducted. The results revealed that SIX1 can enhance Zinc finger E-box binding homeobox 1 (ZEB1) expression and translation, which in turn binds to the Interleukin-6 (IL6) promoter (1138bp-1148bp) to stimulate its transcription, translation, and secretion. Subsequently, IL6 can activate the cell's own STAT3 signaling pathway, promote the phosphorylation of STAT3, promote the downstream signal c-Myc and Cyclin D1 transduction, and promote the expression of stem cell-related transcription factors such as ALDH1A1, OCT4, and SOX2, thereby promoting EMT and stemness. In addition, this study found a new cell interaction model, in which the above-mentioned secreted IL6 can promote the activation of STAT3 signaling pathway, EMT and stemness transformation in the surrounding cells with low expression of SIX1 in a paracrine manner. Our data favored that SIX1/ZEB1/IL6 axis activated the STAT3 signaling pathway of the breast cells themselves and surrounding cells with low SIX1 expression, thus promoting EMT and stemness transformation, activating the malignant progression of the whole breast cancer.
上皮-间质转化（EMT）和乳腺癌干细胞（BCSCs）在乳腺癌机制研究中至关重要。研究表明，无眼同源盒1（SIX1）协调乳腺癌的EMT和BCSCs，同时激活信号转导和转录激活因子3（STAT3）信号通路。然而，SIX1调节STAT3的机制及其通过STAT3信号通路调节EMT和BCSCs的潜力仍未得到探索。在此，进行了细胞、动物、类器官模型以及人类乳腺癌标本的单细胞转录组和空间转录组测序（ST-seq）整合分析。结果显示，SIX1可增强锌指E盒结合同源盒1（ZEB1）的表达和翻译，ZEB1进而与白细胞介素6（IL6）启动子（1138bp - 1148bp）结合，刺激其转录、翻译和分泌。随后，IL6可激活细胞自身的STAT3信号通路，促进STAT3磷酸化，促进下游信号c-Myc和细胞周期蛋白D1的转导，并促进干细胞相关转录因子如醛脱氢酶1A1（ALDH1A1）、八聚体结合转录因子4（OCT4）和性别决定区Y框蛋白2（SOX2）的表达，从而促进EMT和干性。此外，本研究发现了一种新的细胞相互作用模型，其中上述分泌的IL6能够以旁分泌方式促进周围SIX1低表达细胞中STAT3信号通路的激活、EMT和干性转化。我们的数据表明，SIX1/ZEB1/IL6轴激活了乳腺癌细胞自身以及周围SIX1低表达细胞的STAT3信号通路，从而促进EMT和干性转化，激活整个乳腺癌的恶性进展。
