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Front. Oncol. | doi: 10.3389/fonc.2019.01079

Chronic BDE-47 exposure aggravates malignant phenotypes and chemoresistance by activating ERK through ERα and GPR30 in endometrial carcinoma

  • 1Cancer Hospital of Shantou University Medical College, China
  • 2First Affiliated Hospital of Shantou University Medical College, China

Environmental exposures to certain compounds contribute to cell plasticity, tumor progression and even chemoresistance. 2,2',4,4'-tetrabromo diphenyl ether (BDE-47), one of the most frequently detected polybrominated diphenyl ethers (PBDEs) in environmental and biological samples, is a known estrogen disruptor closely associated with the development of hormone-dependent cancers. However, the effect of BDE-47 on endometrial carcinoma (EC), an estrogen-dependent cancer, remains to be elucidated. Mechanisms of estrogen receptor α (ERα) and G-protein-coupled receptor-30 (GPR30) involved in BDE-47 carcinogenesis are yet to be identified. This study aims to investigate the effect of BDE-47 on the invasive phenotype of estrogen-dependent EC cells. BDE-47-treated cells, such as Ishikawa-BDE-47 and HEC-1B-BDE-47 cells, exhibited increased cell viability and enhanced metastatic ability. In vivo studies showed larger tumor volumes and more metastasis in mice injected with Ishikawa-BDE-47 cells compared with parental Ishikawa cells. MTT assay showed that BDE-47 exposure could attenuate sensitivity of EC cells to cisplatin or paclitaxel treatment in vitro. Western blotting revealed overexpression of ERα, GPR30, pEGFR (phosphorylated epidermal growth factor receptor) and pERK (phosphorylated extracellular-regulated protein kinase) in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Knockdown of ERα or GPR30 by small interfering RNA (siRNA) reversed the stimulating effect of BDE-47 on cell growth, migration and invasion of EC cells. Additionally, treatment with pEGFR or pERK inhibitors impaired cell viability, migration and invasion in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Overall, our results indicate that chronic BDE-47 exposure triggers phenotypic plasticity, promote progression and even chemoresistance in EC cells, at least in part, via ERα/GPR30 and EGFR/ERK signaling pathways.

Keywords: 2,2',4,4'-tetrabromo diphenyl ether, endometrial carcinoma, Estrogen receptor α, G-protein-coupled receptor-30, Cisplatin, Paclitaxel, phosphorylated epidermal growth factor receptor, phosphorylated extracellular-regulated protein kinase

Received: 25 Aug 2019; Accepted: 30 Sep 2019.

Copyright: © 2019 Zhang, Peng, Huang, Zhou and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Li Zhou, Cancer Hospital of Shantou University Medical College, Shantou, China,
Mrs. Jiongyu Chen, Cancer Hospital of Shantou University Medical College, Shantou, China,