Journal
BIOCHEMICAL PHARMACOLOGY
Volume 166, Issue -, Pages 23-32Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.05.005
Keywords
Thrombospondin; Lung cancer; Osteoclasts; Bone metastasis; miR-486-3p
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Funding
- Ministry of Science and Technology of Taiwan [MOST 107-2320-B-341-001-MY2, MOST 107-2320-B-030-007]
- Commonwealth Technology Application Project Program of Zhejiang Province [2017C33218]
- National Natural Science Foundation of China [81601850]
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Lung cancers have a predilection for metastasizing to bone. The matricellular glycoprotein thrombospondin (TSP)-2 regulates multiple biological functions and has a critical role in tumor development and metastasis, although its effects are uncertain in lung cancer bone metastasis. This study demonstrates that TSP-2 expression is highly correlated with lung cancer tumor stage and that the TSP-2 neutralizing antibody reduces osteoclast formation in conditioned medium obtained from lung cancer cells. We also found that TSP-2 promotes osteoclastogenesis through the RANKL-dependent pathway and that TSP-2-mediated osteoclastogenesis involves the transactivation of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) via the inhibition of miR-486-3p expression. Osteoblasts played a critical role in osteoclast differentiation and incubation of osteoblasts with TSP-2 altered the RANKL:OPG ratio. Furthermore, TSP-2 knockdown inhibited lung cancer osteolytic metastasis in vivo. TSP-2 appears to be worth targeting for the prevention of bone metastasis in lung cancer.
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