Alternatively activated macrophages (M2) can secrete chemokines, such as chemokine ligand 17 (CCL17), and are associated with promoting tumorigenesis of hepatocellular carcinoma (HCC). This study aimed at investigating the potential role of M2 and CCL17 in progression of HCC. The levels of CCL17 expression in 90 HCC samples were characterized by tissue microarray and stratified for the postsurgical survival. MHCC97L cells were co-cultured with classically activated M1, M2 or CCL17-silencing M2(ccl17mute) or treated with conditional medium (CM) from these cells or CCL17 in vitro. The wound healing, invasion, viability and apoptosis of MHCC97L cells in vitro and tumor growth in vivo were determined. The stemness of MHCC97L cells was examined by sphere formation, flow cytometry and Western blot. The relative expression levels of epithelial-mesenchymal transition (EMT) factors and the Wnt/β-catenin signaling were determined. Higher levels of intratumoral CCL17 expression were significantly associated with clinical pathological characteristics of HCC and with poorer overall survival rates in HCC patients (P < 0.05). High levels of CCR4 were detected in MHCC97L cells. Treatment with the CM from M2 or with CCL17 significantly enhanced the wound healing process, invasion and proliferation of MHCC97L cells in vitro. Co-implantation MHCC97L cells with M2 significantly promoted the growth of MHCC97L tumors in vivo. Co-culture with M2 or treatment with CCL17 enhanced the stemness, EMT process, the TGF-β1 and Wnt/β-catenin signaling in MHCC97L cells. CCL17 promotes the tumorigenesis of HCC and may be a potential biomarker and target for HCC prognosis and therapy.
An improved antitumor effect was observed with the combination therapy of DOX and UTMD, as compared with treatment with DOX, DOX + US or UTMD, which implicates a novel approach for HCC treatment.
Abstract. In the present study, we aimed to ascertain whether there is a correlation between CD206 expression in tumor associated-macrophages (TAMs) and the prognosis of primary hepatocellular carcinomas (HCC) and we investigated the effect of GdCl 3 on HCC. The expression of CD206 in HCC tumor tissues and peri-carcinoma tissues was measured using an array for liver tissues. The effects of GdCl 3 on CD206 expression were examined in stimulated RAW264.7 cells. Target gene expression was evaluated by RT-PCR, western blotting and immunohistochemistry. The Transwell system was used to assess the invasiveness of HCC cells. Finally, we established a mouse model for HCC using N-nitrosodiethylamine (DEN) to determine the effect of GdCl 3 on HCC. Liver tissue array analysis revealed that CD206 was highly expressed in the HCC tissues compared to the level in peri-carcinoma tissue. We found that GdCl 3 suppressed the expression of CD206 in the M2 macrophage phenotype of stimulated RAW264.7 cells with an IC 10 value of 0.07 µg/µl. In addition, GdCl 3 also induced cell apoptosis in the RAW264.7 cells. Addition of GdCl 3 into the culture medium of RAW264.7 cells markedly reduced the invasive ability of Hepa1-6 cells compared to the control cells. Accordingly, GdCl 3 treatment increased the expression of the epithelial-mesenchymal transition (EMT)-related protein E-cadherin while expression of N-cadherin, TWIST and Snail was reduced in IL-4-stimulated cells. Moreover, GdCl 3 treatment inhibited HCC progression in DEN-induced HCC mice, possibly by downregulating CD206. Our findings indicate that CD206 is a potential biomarker for predicting HCC prognosis and that GdCl 3 suppresses HCC progression by downregulating the expression of CD206 in TAMs.
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