1. Bone marrow adipocytes enhance osteolytic bone destruction by activating 1q21.3(S100A7/8/9-IL6R)-TLR4 pathway in lung cancer
- Author
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Guojing Luo, Mengjia Tang, Chang Liu, Li Tian, Ying Xie, Lingyun Lu, Yujue Li, Xijie Yu, Xiang Chen, and Qian Zhao
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Cell type ,Lung Neoplasms ,Bone Marrow Cells ,Osteolysis ,Bone and Bones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Osteoclast ,Cell Line, Tumor ,Internal medicine ,Adipocytes ,medicine ,Animals ,Humans ,Lung cancer ,Mice, Inbred BALB C ,Osteoblasts ,Hematology ,business.industry ,S100 Proteins ,Bone metastasis ,Osteoblast ,General Medicine ,medicine.disease ,Receptors, Interleukin-6 ,Coculture Techniques ,Up-Regulation ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Adipogenesis ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Bone marrow ,business ,Signal Transduction - Abstract
Bone metastasis is the result of complex crosstalk between tumor cells and bone marrow cells. Bone marrow adipocytes (BMAs) are the most abundant cell type in adult bone marrow. Therefore, we explore the effects of BMAs on bone metastasis in lung cancer. RNA-seq was used to compare the mRNA expression level of bone metastatic SBC5 cells and non-bone metastatic SBC3 cells. Rosiglitazone-induced marrow adiposity and intra-femoral injection of SBC5 cells were used to demonstrate the relationship between BMAs and SBC5 cells in vivo. Co-culture system, gene co-expression, gene ontology (GO) enrichment analysis and protein–protein interaction (PPI) network were used to explore the potential mechanism. BMAs specially enhance the invasion of bone metastatic SBC5 instead of non-bone metastatic SBC3 in vitro. SBC5 instead of SBC3 promoted osteoblast and osteoclast differentiation as well as de-differentiation of mature BMAs. Rosiglitazone-induced marrow adiposity significantly enhanced osteolytic lesion induced by SBC5 in vivo. RNA-seq revealed that compared with SBC3, S100A9 and S100A8 genes were the most prominent genes up-regulated in SBC5 cells. High expression of S100A8/9 in SBC5 could be responsible for the crosstalk between lung cancer cells and BMAs. More importantly, interleukin 6 receptor (IL6R), which is adjacent to S100A8/A9 in 1q21.3, was significantly up-regulated by BMAs in vitro. S100A8/A9 (1 μg/ml) could obviously enhance the osteoblastic differentiation and inhibit adipogenic differentiation, whereas TLR4 inhibitor TAK242 (10 μmol/l) significantly attenuated this effect. Our study suggested that bone marrow adipocyte may communicate with lung cancer cells via 1q21.3 (S100A8/A9-IL6R)-TLR4 pathway to promote osteolytic bone destruction. 1q21.3 (S100A8/A9-IL6R) is a potential target for the treatment of lung cancer bone metastasis.
- Published
- 2020