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

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Abstract

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.

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Abbreviations

OS :

osteosarcoma

CCL18 :

chemokine ligand 18

TAM :

tumor-associated macrophage

TME :

tumor microenvironment

UCA1 :

long non-coding RNA urothelial carcinoma associated 1

BME :

bone microenvironment

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Acknowledgements

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

Funding

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

Author information

Author notes

  1. Yang Su, Yan Zhou and Yuan-jue Sun contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Xuhui District, Shanghai City, 200233, China

    Yang Su, Yan Zhou, Ya-Ling Wang, Jun-yi Yin, Yu-jing Huang, Jian-jun Zhang, Ai-na He, Kun Han, Yang Yao & Hai-yan Hu

  2. Department of Medical Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, No. 6600, Nanfeng Road, Fengxian District, Shanghai City, 201499, China

    Yuan-jue Sun

  3. Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Xuhui District, Shanghai City, 200233, China

    Hui-zhen Zhang

  4. Central Laboratory of the Third Affiliated Hospital, Nanchang University, No. 128 Xiangshan North Road, Donghu District, Nanchang City, 330008, Jiangxi Province, China

    Xiao-Bin Lv

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  1. Yang Su
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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.

Corresponding authors

Correspondence to Xiao-Bin Lv or Hai-yan Hu.

Ethics declarations

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.

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Su, Y., Zhou, Y., Sun, Yj. et al. Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1. J Mol Med 97, 49–61 (2019). https://doi.org/10.1007/s00109-018-1711-0

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