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Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer

Tumor Biology volume 37, pages 6371–6378 (2016)Cite this article

Abstract

CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention.

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Author notes

    Affiliations

    1. Department of Thoracic Surgery, Ningbo No.1 Hospital, Ningbo, Zhejiang Province, China

      Jing Guo

    2. Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China

      Xiaofang Yu

    3. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin RD, Shanghai, 200032, China

      Jie Gu, Zongwu Lin, Fengkai Xu, Chunlai Lu & Di Ge

    4. Shanghai No.1 Hospital, Shanghai Jiao Tong University, Shanghai, China

      Guangyin Zhao

    Authors
    1. Jing Guo
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    2. Xiaofang Yu
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    3. Jie Gu
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    4. Zongwu Lin
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    5. Guangyin Zhao
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    6. Fengkai Xu
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    7. Chunlai Lu
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    8. Di Ge
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    Correspondence to Chunlai Lu or Di Ge.

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    Grant support

    The study was supported by Natural Science Foundation of Ningbo, Zhejiang province, China (No. 2014A610218), National Natural Science Foundation of China (No. 81302099), and ZHU XUE Program of Fudan University.

    Additional information

    Jing Guo and Xiaofang Yu contributed equally to this work.

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    Supplementary Figure 1
    figure 7

    Western blotting analysis of phosphorylation AKT in Eca109 cell lines and HEEC cell lines (a). Western blotting analysis of phosphorylation AKT, RhoA, Rac-1, and Cdc42 in HEEC cells, HEEC-vector cells, and HEEC-CXCR4 cells (b). (GIF 24 kb)

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    Supplementary Figure 2
    figure 8

    Expression of CXCR4 in Eca109 with gene downregulation (a). Western blotting analysis of phosphorylation AKT, RhoA, Rac-1, and Cdc42 in Eca109/shCtl cells, Eca109/shCXCR4 cells, and Eca109/shCXCR4-AKT cells (b). The growth curves for Eca109/shCtl cells, Eca109/shCXCR4 cells, and Eca109/shCXCR4-AKT cells in vitro proliferation assays (c). Results of transwell assays showed the representative images of invasive Eca109/shCtl cells, Eca109/shCXCR4 cells, and Eca109/shCXCR4-AKT cells (d). (GIF 70 kb)

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    Cite this article

    Guo, J., Yu, X., Gu, J. et al. Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer. Tumor Biol. 37, 6371–6378 (2016). https://doi.org/10.1007/s13277-015-4504-x

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    • DOI: https://doi.org/10.1007/s13277-015-4504-x

    Keywords

    • CXCR4
    • Chemokines
    • Esophageal neoplasms
    • Neoplasm metastasis
    • PI3K/AKT