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CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer

Oncogene volume 35, pages 2123–2132 (2016)Cite this article

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Abstract

In the tumor microenvironment, chemokine system has a critical role in tumorigenesis and metastasis. The acquisition of stem-like properties by cancer cells is involved in metastasis and drug resistance, which are pivotal problems that result in poor outcomes in patients with lung cancer. Patients with advanced lung cancer present high plasma levels of transforming growth factor-β1 (TGFβ1), which correlate with poor prognostic features. Therefore, TGFβ1 may be important in the tumor microenvironment, where chemokines are widely expressed. However, the role of chemokines in TGFβ1-induced tumor progression still remains unclear. In our study, TGFβ1 upregulated CXC chemokine receptor expression, migration, invasion, epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation in lung adenocarcinoma. We found that CXCR7 was the most upregulated chemokine receptor induced by TGFβ1. CXCR7 knockdown resulted in reduction of migration, invasion and EMT induced by TGFβ1, whereas CXCR4 knockdown did not reverse TGFβ1-promoted EMT. CXCR7 silencing significantly decreased cancer sphere-forming capacity, stem-like properties, chemoresistance and TGFβ1-induced CSC tumor initiation in vivo. In clinical samples, high TGFβ1 and CXCR7 expression was significantly associated with the late stages of lung adenocarcinoma. Moreover, TGFβ1 and CXCR7 coexpression was positively correlated with the CSC marker, CD44, which is associated with lymph node metastasis. Besides, patients with high expression of both CXCR7 and TGFβ1 presented a significantly worse survival rate. These results suggest that the TGFβ1-CXCR7 axis may be a prognostic marker and may provide novel targets for combinational therapies to be used in the treatment of advanced lung cancer in the future.

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Acknowledgements

This study was supported by the Ministry of Science and Technology (MOST 103-2320-B-010-039-MY3, 103-2321-B-010-029), the Ministry of Education (Aim for the Top University Plan), the Tri-Service General Hospital and the National Defense Medical Center (TSGHC-C103-062, TSGH-104-507) and the Taipei City Hospital, Taiwan.

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Authors and Affiliations

  1. Department of Biotechnology and Laboratory Science in Medicine, Department of Education and Research, National Yang-Ming University, Taipei City Hospital, Taipei, Taiwan

    Y-C Wu & K-H Sun

  2. Institute of Marine Biotechnology, National Taiwan Ocean University, Keelung, Taiwan

    S-J Tang

  3. Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei City, Taiwan

    G-H Sun

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Correspondence to G-H Sun or K-H Sun.

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Wu, YC., Tang, SJ., Sun, GH. et al. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer. Oncogene 35, 2123–2132 (2016). https://doi.org/10.1038/onc.2015.274

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