Open Access

ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma

  • Authors:
    • Chi Sun
    • Annan Hu
    • Shengxing Wang
    • Bo Tian
    • Libo Jiang
    • Yun Liang
    • Houlei Wang
    • Jian Dong
  • View Affiliations

  • Published online on: April 13, 2020     https://doi.org/10.3892/ijo.2020.5045
  • Pages: 249-263
  • Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Spinal metastasis occurs in 50‑75% of bone metastases caused by hepatocellular carcinoma (HCC), and HCC‑derived spinal metastasis can lead to a less favorable prognosis. Recently, several studies have demonstrated that C‑X3‑C motif chemokine ligand 1 (CX3CL1) is closely associated with cancer metastasis, and its secretion is modulated by a disintegrin and metalloproteinase 17 (ADAM17). Bone marrow endothelial cells (BMECs) are an essential component of bone marrow. However, little is known about the roles in and effects of BMECs on HCC spinal metastasis. The present study demonstrated that CX3CL1 and C‑X‑C motif chemokine receptor 3 (CXCR3) expression was upregulated in HCC spinal metastases, and that CX3CL1 promoted the migration and invasion of HCC cells to the spine. Western blot analysis revealed that the Src/protein tyrosine kinase 2 (PTK2) axis participated in CX3CL1‑induced HCC cell invasion and migration. CX3CL1 also increased the expression of M2 macrophage markers in THP‑1 monocytes. BMECs promoted the migration and invasion of Hep3B and MHCC97H cells by secreting soluble CX3CL1, whereas the neutralization of CX3CL1 inhibited this enhancement. CX3CL1 enhanced the activation of the phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA)/AKT serine/threonine kinase 1 (AKT1) and Ras homolog family member A (RHOA)/Rho associated coiled‑coil containing protein kinase 2 (ROCK2) signaling pathways through the Src/PTK2 signaling pathway. Furthermore, ADAM17 was activated by mitogen‑activated protein kinase (MAPK)z14 in BMECs and significantly promoted the secretion of CX3CL1. HCC cells enhanced the recruitment and proliferation of BMECs. The overexpression of CX3CR1 facilitated the spinal metastasis of HCC in a mouse model in vivo. In addition, in vivo experiments revealed that BMECs promoted the growth of HCC in the spine. The present study demonstrated that CX3CL1 participates in HCC spinal metastasis, and that BMECs play an important role in the regulation of CX3CL1 in the spinal metastatic environment.

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July 2020
Volume 57 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Sun, C., Hu, A., Wang, S., Tian, B., Jiang, L., Liang, Y. ... Dong, J. (2020). ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma. International Journal of Oncology, 57, 249-263. https://doi.org/10.3892/ijo.2020.5045
MLA
Sun, C., Hu, A., Wang, S., Tian, B., Jiang, L., Liang, Y., Wang, H., Dong, J."ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma". International Journal of Oncology 57.1 (2020): 249-263.
Chicago
Sun, C., Hu, A., Wang, S., Tian, B., Jiang, L., Liang, Y., Wang, H., Dong, J."ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma". International Journal of Oncology 57, no. 1 (2020): 249-263. https://doi.org/10.3892/ijo.2020.5045