Preca Bogdan-Tiberius, Bajdak Karolina, Mock Kerstin, Lehmann Waltraut, Sundararajan Vignesh, Bronsert Peter, Matzge-Ogi Alexandra, Orian-Rousseau Véronique, Brabletz Simone, Brabletz Thomas, Maurer Jochen, Stemmler Marc P
Department of General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Oncotarget. 2017 Feb 14;8(7):11530-11543. doi: 10.18632/oncotarget.14563.
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.
癌症转移是患者生存率低的主要原因。肿瘤细胞通过上皮-间质转化（EMT）从原发性肿瘤中脱离。EMT由关键转录因子介导，包括ZEB1，其由肿瘤细胞与基质细胞和细胞外基质（ECM）的相互作用激活。ZEB1介导的EMT和迁移伴随着大量的细胞重编程和干性表型的获得。然而，对其潜在机制的理解仍不完整。我们发现透明质酸（HA）是一种主要的ECM蛋白聚糖，在乳腺肿瘤中富集，可与CD44s协同支持EMT并增强ZEB1表达。在乳腺癌细胞系中，HA主要由HAS2合成，HAS2已被证明与癌症进展有关。ZEB1和HAS2的表达在各种癌症实体中密切相关，高HAS2水平与早期复发相关。我们发现HAS2、肿瘤细胞衍生的HA和ZEB1形成一个正反馈环，因为HA升高的ZEB1直接激活HAS2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，这是肿瘤细胞诱导的骨溶解的一个指标，有助于骨转移的形成。结合先前确定的ZEB1/ESRP1/CD44s反馈环，我们发现了一种新的自分泌机制，即ZEB1如何加速EMT。
