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A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.

ABSTRACT: 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.

SUBMITTER: Preca BT

PROVIDER: S-EPMC5355283 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.

Preca Bogdan-Tiberius BT Bajdak Karolina K Mock Kerstin K Lehmann Waltraut W Sundararajan Vignesh V Bronsert Peter P Matzge-Ogi Alexandra A Orian-Rousseau Véronique V Brabletz Simone S Brabletz Thomas T Maurer Jochen J Stemmler Marc P MP

Oncotarget 20170201 7

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 ...[more]

PMID: 28086235

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Project description:BackgroundMetastasis is the leading cause of mortality in patients with breast cancer (BC). Studies demonstrate that circular RNAs (circRNAs) were involved in BC progression, while the molecular mechanisms remain largely unclear.MethodsThe microArray circRNA profiles were used to explore the differential expression circRNAs in BC and paracancerous normal tissues, and the quantitative reverse transcription-polymerase chain reaction was used to validate their expression level in clinical samples and cell lines. Nuclear/cytosolic fractionation and fluorescence in situ hybridization (FISH) assays were performed to examine circRRM2 (hsa_circ_0052582) subcellular location. The scratch wound healing and transwell assays were conducted to evaluate the impact of circRRM2 on BC cell migration and invasion. We predicted miRNAs that might bind with cricRRM2 and the downstream target genes using bioinformatics analysis and explored their expression levels and prognostic value in BC. FISH, RNA immunoprecipitation, Co-immunoprecipitation, Western blot, and rescue experiments were implemented to figure out circRRM2 function and underlying mechanisms in BC.ResultsThe present study revealed several aberrant circRNAs in BC tissues and observed that circRRM2 was upregulated in tumor tissues of 40 patients with BC. High circRRM2 was significantly associated with advanced N stage in patients with BC. Gain- and loss- of function experiments revealed that circRRM2 promoted the migration and invasion of cells and functioned as an oncogene in BC. Mechanism studies showed that circRRM2 competed with miR-31-5p/miR-27b-3p to upregulate the IGF2BP1 expression. Furthermore, IGF2BP1 upregulated the circRRM2 level via interacting with MYC, which functioned as the transcriptional factor of circRRM2. Thus, the positive feedback loop that was composed of circRRM2/IGF2BP1/MYC was identified.ConclusionThis study confirms that upregulated circRRM2 functions an oncogenic role in BC metastasis. The positive feedback loop of circRRM2/IGF2BP1/MYC enforces the circRRM2 expression, which might offer a potential target for BC treatment.

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A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.

Publications

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer.

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