Oncotarget

Research Papers:

MiR-101 targets DUSP1 to regulate the TGF-β secretion in sorafenib inhibits macrophage-induced growth of hepatocarcinoma

Xufu Wei _, Chengyong Tang, Xiuxian Lu, Rui Liu, Mi Zhou, Diao He, Daofeng Zheng, Chao Sun and Zhongjun Wu

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Oncotarget. 2015; 6:18389-18405. https://doi.org/10.18632/oncotarget.4089

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Abstract

Xufu Wei1,2, Chengyong Tang3, Xiuxian Lu1, Rui Liu1, Mi Zhou1, Diao He1, Daofeng Zheng1, Chao Sun1, Zhongjun Wu1

1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

2Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, USA

3Department of Clinical Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Correspondence to:

Zhongjun Wu, e-mail: wzjtcy@126.com

Keywords: hepatocellular carcinoma, miR-101, macrophage, DUSP1, sorafenib

Received: March 14, 2015     Accepted: May 18, 2015     Published: May 29, 2015

ABSTRACT

Hepatocellular carcinoma (HCC)-associated macrophages accelerate tumor progression via growth factor release. Therefore, tumor-associated macrophages (TAMs)-initiated signaling cascades are potential therapeutic targets. To better understand anticancer effects of systemic HCC therapy, we studied sorafenib’s effect on macrophage function, focusing on macrophage-related growth factor secretion. We found that dual specificity phosphatase 1 (DUSP1) is a direct target of miR-101. Transfection of miR-101 reduced DUSP1 induction in M2 macrophages and prolonged ERK1/2, p38 and JNK activation, whereas inhibition of miR-101 enhanced DUSP1 expression and decreased ERK1/2, p38 and JNK activation. miR-101 expression was decreased by sorafenib, and inhibition of PI3K/AKT blocked induction of miR-101 by LPS in M2 cells. M2 cells with greater TGF-β and CD206 mRNA expression compared to M1 cells had increased hepatoma growth, metastases and EMT. Sorafenib inhibited miR-101 expression and enhanced DUSP1 expression and lowered TGF-β and CD206 release in M2 cells, slowing macrophage-driven HCC. Our studies demonstrate miR-101 regulates macrophage innate immune responses to LPS via targeting DUSP1. Sorafenib alters macrophage polarization, reduces TGF-β driven cancer growth, metastases and EMT in vitro, and partially inhibits macrophage activation in vivo. Thus, macrophage modulation might explain the anticancer effects of sorafenib.


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