title: MiR-101 targets DUSP1 to regulate the TGF-β secretion in sorafenib inhibits macrophage-induced growth of hepatocarcinoma.
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.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.|Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Xufu
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Clinical Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiuxian
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Diao
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000328:Adult; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D053773:Transforming Growth Factor beta1; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: DUSP1; hepatocellular carcinoma; macrophage; miR-101; sorafenib