Abstract
BackgroundmicroRNAs (miRNAs) have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages. The aim of this study was to find whether miR-26a can suppress M-CSF expression and the recruitment of macrophages.MethodsHepatocellular carcinoma (HCC) cell lines with decreased or increased expression of miR-26a were established in a previous study. M-CSF expression by tumor cells was measured by enzyme-linked immunosorbent assay, and cell migration assays were used to explore the effect of HCC cell lines on macrophage recruitment in vitro. Real-time PCR measured a panel of mRNAs expressed by macrophages. Xenograft models were used to observe tumor growth. Immunohistochemistry was conducted to study the relation between miR-26a expression and M-CSF expression and macrophage recruitment in patients with HCC.ResultsEctopic expression of miR-26a reduced expression of M-CSF. The conditioned medium (CM) from HepG2 cells that overexpressed miR-26a reduced the migration ability of THP-1 cells stimulated by phorbol myristate acetate (PMA) increased expression of interleukin (IL)-12b or IL-23 mRNA and decreased expression of chemokine (C-C motif) ligand (CCL)22, CCL17, and IL-10 mRNA, in comparison to the medium from the parental HepG2 cells. These effects could be interrupted by the PI3K/Akt pathway inhibitor LY294002. Ectopic expression of miR-26a in HCC cells suppressed tumor growth, M-CSF expression, and infiltration of macrophages in tumors. Similar results were also found when using HCCLM3 cells. Furthermore, the expression of miR-26a was inversely correlated with M-CSF expression and macrophage infiltration in tumor tissues from patients with HCC.ConclusionsmiR-26a expression reduced M-CSF expression and recruitment of macrophages in HCC.
Highlights
MicroRNAs have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages
Tumor-associated macrophages (TAMs) originate from circulating monocyte precursors that are recruited to the tumor by tumor-derived signals, including chemokine (C-C motif) ligand 2 (CCL2) and macrophage colony-stimulating factor (M-CSF)
Results miR-26a suppressed the attraction of macrophages by inhibiting M-CSF secretion In a previous study [27], we found miR-26a suppressed the activation of the PI3K/Akt signal pathway
Summary
MicroRNAs (miRNAs) have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages. A unique immune/ inflammation response signature is associated with HCC intrahepatic metastasis, and inflammatory cytokines can predict poor survival of patients with HCC [5, 6] These findings suggest that the immune/inflammation microenvironment may foster the development of HCC. In HCC, most macrophages in the peritumor region exhibit an M2 phenotype, which is probably determined by the tumor cell [12, 13] These macrophages facilitate tumor growth, metastasis, and angiogenesis and are associated with poor patient survival [13,14,15,16]. Some studies have found high expression of M-CSF and its receptor in peritumoral liver tissue, which is associated with poor survival of patients with HCC after curative resection [6, 22]
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