Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1
- 138 Downloads
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.
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.
KeywordsCCL18 Osteosarcoma Macrophage UCA1 EP300 Metastasis
chemokine ligand 18
long non-coding RNA urothelial carcinoma associated 1
We sincerely thank Dr. Binzhi Qian (Edinburgh EH16 4TJ, UK) for his crucial assistance and experimental guidance.
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.
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.
- 2.Friebele JC, Peck J, Pan X, Abdel-Rasoul M, Mayerson JL (2015) Osteosarcoma: a meta-analysis and review of the literature. Am J Orthop (Belle Mead NJ) 44(12):547–553Google Scholar
- 4.Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol Off J Am Soc Clin Oncol 20(3):776–790CrossRefGoogle Scholar
- 18.Lane D, Matte I, Laplante C, Garde-Granger P, Carignan A, Bessette P, Rancourt C, Piche A (2016) CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling. 15(1):58Google Scholar
- 20.Itoh H, Kadomatsu T, Tanoue H, Yugami M, Miyata K, Endo M, Morinaga J, Kobayashi E, Miyamoto T, Kurahashi R, Terada K, Mizuta H, Oike Y (2018) TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. Oncogene 37(22):2903–2920CrossRefGoogle Scholar
- 21.Gomez-Brouchet A, Illac C, Gilhodes J, Bouvier C, Aubert S, Guinebretiere JM, Marie B, Larousserie F, Entz-Werle N, de Pinieux G, Filleron T, Minard V, Minville V, Mascard E, Gouin F, Jimenez M, Ledeley MC, Piperno-Neumann S, Brugieres L, Redini F (2017) CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: an immunohistochemical analysis of the biopsies from the French OS2006 phase 3 trial. Oncoimmunology 6(9):e1331193CrossRefGoogle Scholar
- 23.Chen G, Liang YX, Zhu JG, Fu X, Chen YF, Mo RJ, Zhou L, Fu H, Bi XC, He HC, Yang SB, Wu YD, Jiang FN, Zhong WD (2014) CC chemokine ligand 18 correlates with malignant progression of prostate cancer. Biomed Res Int 2014:230183–230110Google Scholar
- 25.Sakane R, Tsubamoto H, Sakata K, Inoue K, Ogino M, Shibahara H, Hao H, Hirota S (2014) Expression of chemokine ligand 18 in stage IA low-grade endometrial cancer. Anticancer Res 34(10):5331–5336Google Scholar
- 28.Hoffman RM (2017) Patient-derived mouse models of cancer. Patient-derived orthotopic xenografts (PDOX). Anticancer ResGoogle Scholar
- 33.Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, Chen J, Liu X, Wang SK (2015) Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget 6(10):7899–7917Google Scholar
- 36.Wen JJ, Ma YD, Yang GS, Wang GM (2017) Analysis of circulating long non-coding RNA UCA1 as potential biomarkers for diagnosis and prognosis of osteosarcoma. Eur Rev Med Pharmacol Sci 21(3):498–503Google Scholar
- 37.Li T, Xiao Y, Huang T (2018) HIF-1α-induced upregulation of lncRNA UCA1 promotes cell growth in osteosarcoma by inactivating the PTEN/AKT signaling pathway. Oncol Rep 39(3):1072–1080Google Scholar
- 38.Zhu G, Liu X, Su Y, Kong F, Hong X, Lin Z (2018) Knockdown of urothelial carcinoma associated 1 suppressed cell growth and migration through regulating miR-301a and CXCR4 in osteosarcoma MHCC97 cells. Oncol Res. https://doi.org/10.3727/096504018x15201143705855