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Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development

Author

Listed:
  • Patrick Ming-Kuen Tang

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Shuang Zhou

    (The Chinese University of Hong Kong
    Clinical Translational Research Center, Shanghai Pulmonary Hospital
    Tongji University School of Medicine, Tongji University Cancer Institute)

  • Xiao-Ming Meng

    (The Chinese University of Hong Kong)

  • Qing-Ming Wang

    (The Chinese University of Hong Kong)

  • Chun-Jie Li

    (The Chinese University of Hong Kong)

  • Guang-Yu Lian

    (The Chinese University of Hong Kong)

  • Xiao-Ru Huang

    (The Chinese University of Hong Kong)

  • Yong-Jiang Tang

    (The Chinese University of Hong Kong)

  • Xin-Yuan Guan

    (The University of Hong Kong)

  • Bryan Ping-Yen Yan

    (The Chinese University of Hong Kong)

  • Ka-Fai To

    (The Chinese University of Hong Kong)

  • Hui-Yao Lan

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

Abstract

TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3−/− bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities in vivo, and promotes differentiation of NK cells ex vivo. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions in vivo and in vitro. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy.

Suggested Citation

  • Patrick Ming-Kuen Tang & Shuang Zhou & Xiao-Ming Meng & Qing-Ming Wang & Chun-Jie Li & Guang-Yu Lian & Xiao-Ru Huang & Yong-Jiang Tang & Xin-Yuan Guan & Bryan Ping-Yen Yan & Ka-Fai To & Hui-Yao Lan, 2017. "Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14677
    DOI: 10.1038/ncomms14677
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    Cited by:

    1. Francesca Reggiani & Giovanna Talarico & Giulia Gobbi & Elisabetta Sauta & Federica Torricelli & Veronica Manicardi & Eleonora Zanetti & Stefania Orecchioni & Paolo Falvo & Simonetta Piana & Filippo L, 2024. "BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Jeff Yat-Fai Chung & Philip Chiu-Tsun Tang & Max Kam-Kwan Chan & Vivian Weiwen Xue & Xiao-Ru Huang & Calvin Sze-Hang Ng & Dongmei Zhang & Kam-Tong Leung & Chun-Kwok Wong & Tin-Lap Lee & Eric W-F Lam &, 2023. "Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Diptavo Dutta & Yuan He & Ashis Saha & Marios Arvanitis & Alexis Battle & Nilanjan Chatterjee, 2022. "Aggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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