A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer
Copyright policy )A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer
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.
- Helmholtz Association of German Research Centres Germany
- University of Erlangen-Nuremberg Germany
- Wrocław Medical University Poland
- Karlsruhe Institute of Technology Germany
- National University of Singapore Singapore
genetic association, epithelial mesenchymal transition, fluorescent antibody technique, Fluorescent Antibody Technique, Osteoclasts, Kaplan-Meier Estimate, glucuronosyltransferase, feedback system, Polymerase Chain Reaction, synthetase, hyaluronic acid, positive feedback loop, Glucuronosyltransferase, Hermes antigen, bone metastasis, transforming growth factor beta, info:eu-repo/classification/ddc/570, Feedback, Physiological, breast tumor, biology, HAS2 protein, correlational study, 600, Cell Differentiation, gene expression regulation, ZEB1 protein, protein function, Life sciences, Immunohistochemistry, unclassified drug, Gene Expression Regulation, Neoplastic, tumor growth, female, regulator protein, epithelial splicing regulatory protein 1, osteoclast, Female, ddc:570, Research Paper, Life sciences; biology, 570, Chromatin Immunoprecipitation, in vitro study, Epithelial-Mesenchymal Transition, gene activation, Blotting, Western, 610, Breast Neoplasms, Enzyme-Linked Immunosorbent Assay, chromatin immunoprecipitation, cancer prognosis, Article, cancer growth, breast cancer, hyaluronic acid synthase 2, Cell Line, Tumor, breast cancer cell line, Humans, controlled study, Neoplasm Invasiveness, human, gene, HAS2 gene, proteoglycan, human cell, Zinc Finger E-box-Binding Homeobox 1, ZEB1 gene, human tissue, enzyme linked immunosorbent assay, cell differentiation, cancer recurrence, gene expression, transcription factor ZEB1, osteolysis, Hyaluronan Synthases
genetic association, epithelial mesenchymal transition, fluorescent antibody technique, Fluorescent Antibody Technique, Osteoclasts, Kaplan-Meier Estimate, glucuronosyltransferase, feedback system, Polymerase Chain Reaction, synthetase, hyaluronic acid, positive feedback loop, Glucuronosyltransferase, Hermes antigen, bone metastasis, transforming growth factor beta, info:eu-repo/classification/ddc/570, Feedback, Physiological, breast tumor, biology, HAS2 protein, correlational study, 600, Cell Differentiation, gene expression regulation, ZEB1 protein, protein function, Life sciences, Immunohistochemistry, unclassified drug, Gene Expression Regulation, Neoplastic, tumor growth, female, regulator protein, epithelial splicing regulatory protein 1, osteoclast, Female, ddc:570, Research Paper, Life sciences; biology, 570, Chromatin Immunoprecipitation, in vitro study, Epithelial-Mesenchymal Transition, gene activation, Blotting, Western, 610, Breast Neoplasms, Enzyme-Linked Immunosorbent Assay, chromatin immunoprecipitation, cancer prognosis, Article, cancer growth, breast cancer, hyaluronic acid synthase 2, Cell Line, Tumor, breast cancer cell line, Humans, controlled study, Neoplasm Invasiveness, human, gene, HAS2 gene, proteoglycan, human cell, Zinc Finger E-box-Binding Homeobox 1, ZEB1 gene, human tissue, enzyme linked immunosorbent assay, cell differentiation, cancer recurrence, gene expression, transcription factor ZEB1, osteolysis, Hyaluronan Synthases
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