Journal of Molecular Medicine

, Volume 97, Issue 1, pp 49–61 | Cite as

Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1

  • Yang Su
  • Yan Zhou
  • Yuan-jue Sun
  • Ya-Ling Wang
  • Jun-yi Yin
  • Yu-jing Huang
  • Jian-jun Zhang
  • Ai-na He
  • Kun Han
  • Hui-zhen Zhang
  • Yang Yao
  • Xiao-Bin LvEmail author
  • Hai-yan HuEmail author
Original Article


Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/β-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/β-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS.

Key messages

  • CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/β-catenin pathway.

  • CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients.

  • CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.


CCL18 Osteosarcoma Macrophage UCA1 EP300 Metastasis 





chemokine ligand 18


tumor-associated macrophage


tumor microenvironment


long non-coding RNA urothelial carcinoma associated 1


bone microenvironment



We sincerely thank Dr. Binzhi Qian (Edinburgh EH16 4TJ, UK) for his crucial assistance and experimental guidance.

Author contributions

Y.S, Y.Z., and Y. S. performed the experiments and wrote the paper. Y. W., J. Y., Y. H., and J. Z. analyzed the data. A. H., K. H., and H. Z. carried out the sample collection and preparation. Y. Y. participated in the literature search and manuscript revision. H. H. and X. L. conceived and designed the research.

Funding information

This work was supported by the National Natural Science Foundation of China (Nos. 81503396 and 81372873).

Compliance with ethical standards

The study was carried out in accordance with the World Medical Association Declaration of Helsinki and obtained approval from the local ethics committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. Written informed consent was obtained from all patients. The animal experimental operations were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Supplementary material

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ESM 1 (DOCX 17 kb)
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Supplemental Fig. 1

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High-resolution image (TIF 92 kb)
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Supplemental Fig. 2

(PNG 413 kb)

109_2018_1711_MOESM3_ESM.tif (1.9 mb)
High-resolution image (TIF 1989 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yang Su
    • 1
  • Yan Zhou
    • 1
  • Yuan-jue Sun
    • 2
  • Ya-Ling Wang
    • 1
  • Jun-yi Yin
    • 1
  • Yu-jing Huang
    • 1
  • Jian-jun Zhang
    • 1
  • Ai-na He
    • 1
  • Kun Han
    • 1
  • Hui-zhen Zhang
    • 3
  • Yang Yao
    • 1
  • Xiao-Bin Lv
    • 4
    Email author
  • Hai-yan Hu
    • 1
    Email author
  1. 1.Department of OncologyShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai CityChina
  2. 2.Department of Medical OncologyShanghai Jiao Tong University Affiliated Sixth People’s Hospital South CampusShanghai CityChina
  3. 3.Department of PathologyShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai CityChina
  4. 4.Central Laboratory of the Third Affiliated HospitalNanchang UniversityNanchang CityChina

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