title: Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea.|Department of Applied Life Science, The Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Applied Life Science, The Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
authors.forename: Junhee
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea.|Department of Applied Life Science, The Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
authors.forename: Sun Kyoung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Dental Hygiene, Kyungpook National University, Sangju, Korea.
authors.forename: Ki Rim
authors.initials: KR
authors.lastname: Kim
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea.|Department of Applied Life Science, The Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea.|Department of Applied Life Science, The Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
authors.forename: Won-Yoon
authors.initials: WY
authors.lastname: Chung
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000556:secondary*; D054415:Chemokine CCL19 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054371:Chemokine CXCL11 / Q000096:biosynthesis; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D014408:Biomarkers, Tumor; D054415:Chemokine CCL19; D018946:Chemokine CCL5; D054371:Chemokine CXCL11; D050677:Core Binding Factor Alpha 3 Subunit
keywords: RANKL; RUNX3; RUNX3-regulated chemokines; cancer-mediated bone resorption; non-small cell lung cancer; osteoprotegerin