Oncotarget

Research Papers:

Let-7b inhibits cancer-promoting effects of breast cancer-associated fibroblasts through IL-8 repression

Bothina Al-Harbi, Siti-Fauziah Hendrayani, Gabriela Silva and Abdelilah Aboussekhra _

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Oncotarget. 2018; 9:17825-17838. https://doi.org/10.18632/oncotarget.24895

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Abstract

Bothina Al-Harbi1, Siti-Fauziah Hendrayani1, Gabriela Silva1,2 and Abdelilah Aboussekhra1

1Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

2Current/Present address: Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal

Correspondence to:

Abdelilah Aboussekhra, email: [email protected]

Keywords: breast cancer; let-7b; cancer-associated fibroblasts; IL-8

Received: November 26, 2017    Accepted: February 27, 2018    Published: April 03, 2018

ABSTRACT

Cancer-associated fibroblasts (CAFs) are major players in the development and spread of breast carcinomas through non-cell-autonomous signaling. These paracrine effects are under the control of several genes and microRNAs. We present here clear evidence that let-7b, a tumor suppressor microRNA, plays key roles in the persistent activation of breast stromal fibroblasts and their functional interplay with cancer cells. We have first shown that let-7b is down-regulated in CAFs as compared to their corresponding normal adjacent fibroblasts, and transient specific let-7b inhibition permanently activated breast fibroblasts through induction of the IL-6-related positive feedback loop. More importantly, let-7b-deficient cells promoted the epithelial-to-mesenchymal transition process in breast cancer cells in an IL-8-dependent manner, and also enhanced orthotopic tumor growth in vivo. On the other hand, overexpression of let-7b by mimic permanently suppressed breast myofibroblasts through blocking the positive feedback loop, which inhibited their paracrine pro-carcinogenic effects. Furthermore, we have shown that let-7b negatively controls IL-8, which showed higher expression in the majority of CAF cells as compared to their adjacent normal counterparts, indicating that IL-8 plays a major role in the carcinoma/stroma cross-talk. These findings support targeting active stromal fibroblasts through restoration of let-7b/IL-8 expression as a therapeutic option for breast carcinomas.


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