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; Amato J. Giaccia

doi:10.1038/s41467-021-24631-6

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, Amato J. Giaccia

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

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.

Original language	English (US)
Article number	4308
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24631-6
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Moon, E. J., Mello, S. S., Li, C. G., Chi, J. T., Thakkar, K., Kirkland, J. G., Lagory, E. L., Lee, I. J., Diep, A. N., Miao, Y., Rafat, M., Vilalta, M., Castellini, L., Krieg, A. J., Graves, E. E., Attardi, L. D., & Giaccia, A. J. (2021). The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature communications, 12(1), Article 4308. https://doi.org/10.1038/s41467-021-24631-6

Moon, EJ, Mello, SS, Li, CG, Chi, JT, Thakkar, K, Kirkland, JG, Lagory, EL, Lee, IJ, Diep, AN, Miao, Y, Rafat, M, Vilalta, M, Castellini, L, Krieg, AJ, Graves, EE, Attardi, LD & Giaccia, AJ 2021, 'The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling', Nature communications, vol. 12, no. 1, 4308. https://doi.org/10.1038/s41467-021-24631-6

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title = "The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling",

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.",

author = "Moon, {Eui Jung} and Mello, {Stephano S.} and Li, {Caiyun G.} and Chi, {Jen Tsan} and Kaushik Thakkar and Kirkland, {Jacob G.} and Lagory, {Edward L.} and Lee, {Ik Jae} and Diep, {Anh N.} and Yu Miao and Marjan Rafat and Marta Vilalta and Laura Castellini and Krieg, {Adam J.} and Graves, {Edward E.} and Attardi, {Laura D.} and Giaccia, {Amato J.}",

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doi = "10.1038/s41467-021-24631-6",

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AU - Mello, Stephano S.

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AU - Chi, Jen Tsan

AU - Thakkar, Kaushik

AU - Kirkland, Jacob G.

AU - Lagory, Edward L.

AU - Lee, Ik Jae

AU - Diep, Anh N.

AU - Miao, Yu

AU - Rafat, Marjan

AU - Vilalta, Marta

AU - Castellini, Laura

AU - Krieg, Adam J.

AU - Graves, Edward E.

AU - Attardi, Laura D.

AU - Giaccia, Amato J.

PY - 2021/12/1

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N2 - 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.

AB - 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.

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

Abstract

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