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ITGA2 is a target of miR-206 promoting cancer stemness and lung metastasis through enhanced ACLY and CCND1 expression in triple negative breast cancer

Valery Adorno-Cruz, Andrew D. Hoffmann, Xia Liu, Brian Wray, Ruth A. Keri, View ORCID ProfileHuiping Liu
doi: https://doi.org/10.1101/583062
Valery Adorno-Cruz
1Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Andrew D. Hoffmann
2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Xia Liu
2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3Cleveland Clinic Foundation, Cleveland, OH, USA.
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Brian Wray
4Bioinformatic Core, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Ruth A. Keri
1Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
5Department of Genetics and Genome Sciences, the Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH, USA.
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Huiping Liu
2Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
6Department of Medicine, the Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
7Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
8Department of Pathology and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
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Abstract

Accumulating evidence demonstrates that cancer stemness is essential for both tumor development and progression, regulated by multi-layer factors at genetic, epigenetic and micro-environmental levels. However, how to target stemness-driven plasticity and eliminate metastasis remains one of the biggest challenges in the clinic. We aim to identify novel molecular mechanisms underlying stemness of triple negative breast cancer (TNBC) which frequently metastasizes to the visceral organs but lacks targeted therapies. Following our previous discovery of miR-206 as an epigenetic suppressor of tumorigenesis and metastasis, we now report that the integrin receptor CD49b-encoding ITGA2 is an oncogenic target of miR-206 in TNBC. ITGA2 knockdown abolished cancer stemness (mammosphere formation, pluripotency marker expression, and FAK phosphorylation), inhibited cell cycling, compromised migration and invasion, and thereby decreasing lung metastasis of TNBC. RNA sequencing analyses of breast cancer cells revealed that ITGA2 knockdown inhibits gene expression essential for both classical integrin-regulated pathways (cell cycle, wounding response, protein kinase, etc) and newly identified pathways such as lipid metabolism. Notably, ACLY-encoded ATP citrate lyase is one of the top targets in CD49b-regulated lipid metabolism and CCND1-encoded Cyclin D1 represents regulation of cell cycle and many other pathways. ACLY, known to catalyze the formation of cytosolic acetyl-CoA for fatty acid biosynthesis, is indispensable for cancer stemness. Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest. High expression levels of the ITGA2/ACLY/CCND1 axis are correlated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifies ITGA2 as a potential therapeutic target of TNBC stemness and metastasis.

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  • Conflicts of Interest:

    There is no conflict of interest for the authors of this manuscript.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 19, 2019.
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ITGA2 is a target of miR-206 promoting cancer stemness and lung metastasis through enhanced ACLY and CCND1 expression in triple negative breast cancer
Valery Adorno-Cruz, Andrew D. Hoffmann, Xia Liu, Brian Wray, Ruth A. Keri, Huiping Liu
bioRxiv 583062; doi: https://doi.org/10.1101/583062
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ITGA2 is a target of miR-206 promoting cancer stemness and lung metastasis through enhanced ACLY and CCND1 expression in triple negative breast cancer
Valery Adorno-Cruz, Andrew D. Hoffmann, Xia Liu, Brian Wray, Ruth A. Keri, Huiping Liu
bioRxiv 583062; doi: https://doi.org/10.1101/583062

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