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RAC1-GTP promotes epithelial-mesenchymal transition and invasion of colorectal cancer by activation of STAT3

Laboratory Investigation (2018) | Download Citation

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in initiating tumor invasion and metastasis of colorectal cancer (CRC), although the underlying mechanisms remain to be clarified. Herein, we demonstrate that the active form of Rac family small GTPase 1 (RAC1-GTP) is overexpressed in CRCs and promotes the EMT-mediated invasion of CRC cells through activation of the signal transducers and activators of transcription 3 (STAT3) pathway. Increased expression of RAC1-GTP in CRC tissues was positively correlated with the TNM stages of CRCs and indicated poor prognosis of CRC patients. Targeting RAC1-GTP activity by its specific inhibitor NSC23766 markedly suppressed the migration and invasion of CRC cells. Mechanistically, RAC1-GTP directly interacted with STAT3 to promote STAT3 phosphorylation, thus promoted EMT of CRC cells. Enforced expression of constitutively activated STAT3 (STAT3-C) abrogated the suppressive effect of RAC1-GTP disruption on the migration and invasion of CRC cells. Importantly, NSC23766 disrupted EMT in CRC cells and significantly diminished growth of CRC xenografts. Taken together, our data indicate that RAC1-GTP is an important player in EMT-mediated tumor invasion and a potential therapeutic target for CRCs.

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Acknowledgements

This research was supported by the grant from China National Natural Science Foundation of China (No. 81402460).

Author information

Affiliations

  1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    • Kai Zhou
    • , Jun Rao
    • , Zhi-hua Zhou
    • , Xiao-hong Yao
    • , Feng Wu
    • , Jing Yang
    • , Lang Yang
    • , Xia Zhang
    • , You-hong Cui
    • , Xiu-Wu Bian
    • , Yu Shi
    •  & Yi-fang Ping
  2. Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China

    • Kai Zhou
    • , Jun Rao
    • , Zhi-hua Zhou
    • , Xiao-hong Yao
    • , Feng Wu
    • , Jing Yang
    • , Xia Zhang
    • , You-hong Cui
    • , Xiu-Wu Bian
    • , Yu Shi
    •  & Yi-fang Ping
  3. Department of Hematology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    • Jun Rao
  4. Department of Gastroenterology, Army General Hospital of PLA, Beijing, 100700, China

    • Lang Yang

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The authors declare that they have no conflict of interest.

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Correspondence to Xiu-Wu Bian or Yu Shi or Yi-fang Ping.

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DOI

https://doi.org/10.1038/s41374-018-0071-2

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