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The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells
Romaine I. Fernando, … , Jeffrey Schlom, Claudia Palena
Romaine I. Fernando, … , Jeffrey Schlom, Claudia Palena
Published January 11, 2010
Citation Information: J Clin Invest. 2010;120(2):533-544. https://doi.org/10.1172/JCI38379.
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Research Article Oncology

The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells

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Abstract

Metastatic disease is responsible for the majority of human cancer deaths. Understanding the molecular mechanisms of metastasis is a major step in designing effective cancer therapeutics. Here we show that the T-box transcription factor Brachyury induces in tumor cells epithelial-mesenchymal transition (EMT), an important step in the progression of primary tumors toward metastasis. Overexpression of Brachyury in human carcinoma cells induced changes characteristic of EMT, including upregulation of mesenchymal markers, downregulation of epithelial markers, and an increase in cell migration and invasion. Brachyury overexpression also repressed E-cadherin transcription, an effect partially mediated by Slug. Conversely, inhibition of Brachyury resulted in downregulation of mesenchymal markers and loss of cell migration and invasion and diminished the ability of human tumor cells to form lung metastases in a xenograft model. Furthermore, we found Brachyury to be overexpressed in various human tumor tissues and tumor cell lines compared with normal tissues. We also determined that the percentage of human lung tumor tissues positive for Brachyury expression increased with the stage of the tumor, indicating a potential association between Brachyury and tumor progression. The selective expression of Brachyury in tumor cells and its role in EMT and cancer progression suggest that Brachyury may be an attractive target for antitumor therapies.

Authors

Romaine I. Fernando, Mary Litzinger, Paola Trono, Duane H. Hamilton, Jeffrey Schlom, Claudia Palena

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Figure 6

Brachyury inhibition reduces tumor metastasis.

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Brachyury inhibition reduces tumor metastasis.
(A) H460 cells stably tra...
(A) H460 cells stably transfected with con.shRNA (circles) or Br.shRNA vectors (triangles) were assessed for cell proliferation and survival by MTT assay. Three independent experiments showed comparable results; results from 1 experiment are shown. ***P = 0.0003 for con.shRNA versus Br.shRNA. Western blot shows cyclin D1 and β-actin expression. (B) Subcutaneous tumors were induced by injection of 4 × 106 of H460 cells in HBSS admixed with 50% (v/v) Matrigel. Graph shows volumes from 8 tumors at day 15 after tumor implantation. (C) cDNA from tumors in B were analyzed by real-time PCR for indicated markers. (D) Lungs from animals bearing subcutaneous tumors were collected at day 15 after tumor implantation, homogenized, and cultured in puromycin-containing medium. Graph shows visible colony counts. (E) Mice were inoculated with 7.5 × 105 H460 cells transfected as indicated via tail vein. Forty-five days after tumor implantation, animals were euthanized, and lungs were evaluated for tumor nodules. Graph shows results from 3 independent experiments. Experiments 1–3 are denoted by black, gray, and white circles (con.shRNA) and triangles (Br.shRNA), respectively. Statistical difference between treatment groups was analyzed by pooled results of the above experiments. Two representative lungs from each group are shown for comparison. White outlines and black arrowheads indicate tumor masses.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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