Oncotarget

Research Papers:

Let-7g suppresses both canonical and non-canonical NF-κB pathways in macrophages leading to anti-atherosclerosis

Yung-Song Wang, Edward Hsi, Hsin-Yun Cheng, Shih-Hsien Hsu, Yi-Chu Liao and Suh-Hang H. Juo _

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Oncotarget. 2017; 8:101026-101041. https://doi.org/10.18632/oncotarget.18197

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Abstract

Yung-Song Wang1,2, Edward Hsi3, Hsin-Yun Cheng4, Shih-Hsien Hsu4, Yi-Chu Liao5,6 and Suh-Hang H. Juo3,7,8,9

1Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan

2Department of Life Science, National Taiwan University, Taipei, Taiwan

3Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

4Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan

6Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan

7Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

8Institute of New Drug Development, China Medical University, Taichung, Taiwan

9Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan

Correspondence to:

Suh-Hang H. Juo, email: hjuo@mail.cmu.edu.tw

Keywords: atherosclerosis, foam cell, let-7, microRNA, macrophage

Received: January 24, 2017     Accepted: April 29, 2017     Published: May 23, 2017

ABSTRACT

Transformation of macrophages to foam cells contributes to atherosclerosis. Here, we report that let-7g reduces macrophage transformation and alleviates foam cell apoptosis by suppressing both canonical and non-canonical NF-κB pathways. In the canonical pathway, let-7g inhibits phosphorylation of IKKβ and IκB, down-regulates SREBF2 and miR-33a, and up-regulates ABCA1. In the non-canonical pathway, let-7g directly knocks down MEKK1, IKKα and ablates IKKα phosphorylation. Let-7g’s effects in macrophages can be almost completely blocked by inactivation of NF-κB signaling, which suggests that let-7g’s effects are primarily mediated through the suppression of NF-κB pathways. NF-κB has been reported to directly activate lin28 transcription, and lin28 is a well-known negative regulator for let-7 biogenesis. Therefore, there is negative feedback between NF-κB and let-7g. Additional macrophages-specific NF-κB knockout in the apoE deficiency mice reduces atherosclerotic lesion by 85%. Let-7g also suppresses p53-dependent apoptosis. Altogether, sufficient let-7g levels are important to prevent NF-κB over-activation in macrophages and to prevent atherosclerosis.


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