GdCl3 suppresses the malignant potential of hepatocellular carcinoma by inhibiting the expression of CD206 in tumor‑associated macrophages.
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 GdCl3 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 GdCl3 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 GdCl3 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 GdCl3 suppressed the expression of CD206 in the M2 macrophage phenotype of stimulated RAW264.7 cells with an IC10 value of 0.07 µg/µl. In addition, GdCl3 also induced cell apoptosis in the RAW264.7 cells. Addition of GdCl3 into the culture medium of RAW264.7 cells markedly reduced the invasive ability of Hepa1-6 cells compared to the control cells. Accordingly, GdCl3 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, GdCl3 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 GdCl3 suppresses HCC progression by downregulating the expression of CD206 in TAMs.
Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Fangyu
F
Zhu
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Xiangnan
X
Li
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Yong
Y
Jiang
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Haoran
H
Zhu
Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Haolong
H
Zhang
Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Chengyao
C
Zhang
Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Yu
Y
Zhao
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Fang
F
Luo
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005682:Gadolinium / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D011379:Prognosis; D000067996:RAW 264.7 Cells; D011971:Receptors, Immunologic / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C573543:MRC1 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D005682:Gadolinium; C038958:gadolinium chloride