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Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma

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Abstract

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 M2ccl17mute 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.

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Funding

This study was funded by the grants from the National Natural Science Foundation (Grant Nos. 81071882 and 81372481) and the National Key Clinical Specialties Construction Program of China.

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Authors and Affiliations

  1. Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Fangyu Zhu, Siyu Chen, Qiu Zeng & Yu Zhao

  2. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Fangyu Zhu, Xiangnan Li & Fang Luo

Authors
  1. Fangyu Zhu
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  2. Xiangnan Li
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  3. Siyu Chen
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  4. Qiu Zeng
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Correspondence to Fang Luo.

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Authors declare no conflicts of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients included in the study gave written consent themselves. For studies with animals, we declare all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Zhu, F., Li, X., Chen, S. et al. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol 33, 17 (2016). https://doi.org/10.1007/s12032-016-0729-9

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  • DOI: https://doi.org/10.1007/s12032-016-0729-9

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