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

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 Castellini, Adam J. Krieg, Edward E. Graves, Laura D. Attardi and Amato J. Giaccia ()
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Eui Jung Moon: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
Stephano S. Mello: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University
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
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24631-6

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