A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.
A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.
复制标题
DOI：
10.18632/oncotarget.14563
复制
发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Stemmler MP
中科院分区：
文献类型：
--
作者：
Preca BT;Bajdak K;Mock K;Lehmann W;Sundararajan V;Bronsert P;Matzge-Ogi A;Orian-Rousseau V;Brabletz S;Brabletz T;Maurer J;Stemmler MP
肿瘤转移是影响患者生存率的主要原因。肿瘤细胞通过诱导上皮-间质转化（EMT）从原发性肿瘤分层。EMT由关键转录因子介导，包括ZEB 1，通过肿瘤细胞与基质细胞和细胞外基质（ECM）的相互作用激活。ZEB 1介导的EMT和运动性伴随着大量的细胞重编程和干性表型的获得。然而，对潜在机制的理解仍然不完整。我们鉴定了透明质酸（HA），一种主要的ECM蛋白聚糖，并在乳腺肿瘤中富集，以支持EMT并与CD 44 s合作增强ZEB 1表达。在乳腺癌细胞系中，HA主要由HAS 2合成，其已经显示与癌症进展有关。ZEB 1和HAS 2表达在各种癌症实体中强烈相关，高HAS 2水平与早期复发相关。我们鉴定了HAS 2、肿瘤细胞来源的HA和ZEB 1形成正反馈环，因为HA升高的ZEB 1直接激活HAS 2表达。在体外分化模型中，乳腺癌细胞的HA条件培养基增强破骨细胞形成，破骨细胞形成是促进骨转移形成的肿瘤细胞诱导的骨质溶解的指标。结合先前鉴定的ZEB 1/ESRP 1/CD 44 s反馈回路，我们发现了ZEB 1如何加速EMT的新的自分泌机制。
Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT.