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Sema4D expression and secretion are increased by HIF-1α and inhibit osteogenesis in bone metastases of lung cancer

  • Wu-gui Chen
  • Jing Sun
  • Wei-wei Shen
  • Si-zhen Yang
  • Ying Zhang
  • Xu Hu
  • Hao Qiu
  • Shang-cheng XuEmail author
  • Tong-wei ChuEmail author
Research Paper

Abstract

Most lung cancer bone metastasis are characterized by osteolytic destruction and osteoblastic activity is significantly decreased, suggesting that hypoxia may play a critical role in the process, but the underlying mechanisms remain unknown. Semaphorin 4D (Sema4D) is a recently discovered osteogenic inhibitory factor that is expressed at high levels in lung cancers. Here, CoCl2-induced hypoxia significantly enhanced the inhibitory effect of lung cancer cell conditioned media on osteoblast differentiation by inducing the expression and secretion of Sema4D in a HIF-1α- but not HIF-2α-dependent manner. Moreover, HIF-1α directly regulated Sema4D expression by binding to bases 1171 to 798 in the Sema4D promoter. Furthermore, hypoxia increased Sema4D secretion by upregulating a disintegrin and metalloproteinase 17 (ADAM17) expression in lung cancer in a HIF-1α-dependent manner. In bone metastasis samples from 49 patients with lung cancer, Sema4D and ADAM17 expression significantly correlated with HIF-1α expression and strongly correlated with a poor differentiation status and osteolytic bone destruction. These results provide the first evidence that HIF-1α-induced Sema4D expression and secretion play important roles in lung cancer osteolytic bone metastasis by inhibiting osteoblast differentiation, thereby providing potential strategies for the treatment of bone metastasis via targeting osteoblasts.

Keywords

Hypoxia-inducing factor Semaphorin 4D ADAM17 Bone metastasis Osteoblast Lung cancer 

Abbreviations

Sema4D

Semaphorin 4D

HIF-1α

Hypoxia-inducible factor-1α

HIF-2α

Hypoxia-inducible factor-2α

ADAM17

A disintegrin and metalloproteinase-17

DTCs

Disseminated tumor cells

PTHrP

Parathyroid hormone-related protein

IL

Interleukin

TNF-α

Tumor necrosis factor-α

RANKL

Receptor activator of NF-κB ligand

CM

Conditioned media

HRE

Hypoxia response elements

SDF-1

Stromal cell-derived factor-1

VEGF

Vascular endothelial growth factor

MCP-1

Monocyte chemotactic protein-1

DKK1

Dickkopf 1 gene

MIP-2

Macrophage inflammatory protein-2

TGF-β

Transforming growth factor-β

Notes

Acknowledgements

We are grateful for the valuable assistance provided by Dr. Wei Xie (Department of central laboratory, Xinqiao Hospital, Army Medical University, Chongqing, China), Xiao-Jian Niu, MS, Wei Liu, MS, and Tao-song Li, MS (Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, China) during the study. This research was supported by the National Natural Science Foundation of China (Grant Number 81570800) and the National Natural Youth Science Fund of China (Grant Number 81501853).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10585_2018_9951_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 KB)

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Orthopedics, Xinqiao HospitalArmy Medical UniversityChongqingChina
  2. 2.Department of OrthopedicsLanzhou Military Region General HospitalLanzhouChina
  3. 3.The Center of Laboratory MedicineThe Sixth People’s Hospital of ChongqingChongqingChina

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