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Non‐small cell lung cancer ( NSCLC ) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis.  RUNX3  functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre‐invasive lesions. Here, we show that  RUNX3  and  RUNX3 ‐regulated chemokines are linked to  NSCLC ‐mediated bone resorption. Notably, the receptor activator of nuclear factor‐ κB  ligand ( RANKL )/osteoprotegerin ( OPG ) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from  RUNX3 ‐knockdown  NSCLC  cells. We aimed to identify  RUNX3 ‐regulated factors that modify the osteoblastic  RANKL / OPG  ratio and found that  RUNX3  knockdown led to  CCL5  up‐regulation and down‐regulation of  CCL19  and  CXCL11  in  NSCLC  cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received  RUNX3 ‐knockdown cells. In response to  RUNX3  knockdown, serum and tissue levels of  CCL5  increased, whereas  CCL19  and  CXCL11  decreased. Furthermore,  CCL5  increased the proliferation, migration, and invasion of lung cancer cells in a dose‐dependent manner; however,  CCL19  and  CXCL11  did not show any significant effects. The  RANKL / OPG  ratio in osteoblastic cells was increased by  CCL5  but reduced by  CCL19  and  CXCL11 .  CCL5  promoted osteoclast differentiation, but  CCL19  and  CXCL11  reduced osteoclastogenesis in  RANKL ‐treated bone marrow macrophages. These findings suggest that  RUNX3  and related chemokines are useful markers for the prediction and/or treatment of  NSCLC ‐induced bone destruction. © 2015 The Authors.  The Journal of Pathology  published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Loss of RUNX3 expression promotes cancer‐associated bone destruction by regulating CCL5 , CCL19 and CXCL11 in non‐small cell lung cancer