PMID- 32319605
OWN - NLM
STAT- MEDLINE
DCOM- 20210308
LR  - 20210915
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 57
IP  - 1
DP  - 2020 Jul
TI  - ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells 
      promotes spinal metastasis from hepatocellular carcinoma.
PG  - 249-263
LID - 10.3892/ijo.2020.5045 [doi]
AB  - 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.
FAU - Sun, Chi
AU  - Sun C
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Hu, Annan
AU  - Hu A
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Wang, Shengxing
AU  - Wang S
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Tian, Bo
AU  - Tian B
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Jiang, Libo
AU  - Jiang L
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Liang, Yun
AU  - Liang Y
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Wang, Houlei
AU  - Wang H
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
FAU - Dong, Jian
AU  - Dong J
AD  - Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 
      200032, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20200413
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (CX3CL1 protein, human)
RN  - 0 (CXCR3 protein, human)
RN  - 0 (Chemokine CX3CL1)
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, CXCR3)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - ADAM17 Protein/genetics/*metabolism
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Bone Marrow/pathology
MH  - Carcinoma, Hepatocellular/*secondary
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects/genetics
MH  - Chemokine CX3CL1/antagonists & inhibitors/*metabolism
MH  - Endothelial Progenitor Cells/*metabolism
MH  - Focal Adhesion Kinase 1/metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Imidazoles
MH  - Liver Neoplasms/*pathology
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism
MH  - Pyridines
MH  - RNA, Small Interfering/metabolism
MH  - Receptors, CXCR3/metabolism
MH  - Signal Transduction/drug effects/genetics
MH  - Spinal Neoplasms/*secondary
MH  - Spine/pathology
MH  - Tumor Microenvironment
PMC - PMC7252465
OTO - NOTNLM
OT  - spinal metastasis
OT  - hepatocellular carcinoma
OT  - bone marrow endothelial cells
OT  - C-X3-C motif chemokine ligand 1
OT  - a disintegrin and metalloproteinase 17
EDAT- 2020/04/23 06:00
MHDA- 2021/03/09 06:00
PMCR- 2020/04/13
CRDT- 2020/04/23 06:00
PHST- 2019/09/27 00:00 [received]
PHST- 2020/03/30 00:00 [accepted]
PHST- 2020/04/23 06:00 [pubmed]
PHST- 2021/03/09 06:00 [medline]
PHST- 2020/04/23 06:00 [entrez]
PHST- 2020/04/13 00:00 [pmc-release]
AID - ijo-57-01-0249 [pii]
AID - 10.3892/ijo.2020.5045 [doi]
PST - ppublish
SO  - Int J Oncol. 2020 Jul;57(1):249-263. doi: 10.3892/ijo.2020.5045. Epub 2020 Apr 
      13.