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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

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  • Eui Jung Moon

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
    MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford)

  • Stephano S. Mello

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
    University of Rochester Medical Center)

  • Caiyun G. Li

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Jen-Tsan Chi

    (Duke University)

  • Kaushik Thakkar

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Jacob G. Kirkland

    (Stanford University
    Oklahoma Medical Research Foundation)

  • Edward L. Lagory

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Ik Jae Lee

    (Yonsei Cancer Center)

  • Anh N. Diep

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Yu Miao

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Marjan Rafat

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
    Vanderbilt University)

  • Marta Vilalta

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Laura Castellini

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Adam J. Krieg

    (Oregon Health and Sciences University)

  • Edward E. Graves

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Laura D. Attardi

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University)

  • Amato J. Giaccia

    (Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
    MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford)

Abstract

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

Suggested Citation

  • Eui Jung Moon & Stephano S. Mello & Caiyun G. Li & Jen-Tsan Chi & Kaushik Thakkar & Jacob G. Kirkland & Edward L. Lagory & Ik Jae Lee & Anh N. Diep & Yu Miao & Marjan Rafat & Marta Vilalta & Laura Cas, 2021. "The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24631-6
    DOI: 10.1038/s41467-021-24631-6
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    References listed on IDEAS

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    1. Balázs Győrffy & Pawel Surowiak & Jan Budczies & András Lánczky, 2013. "Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-8, December.
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