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

Authors
 Hyun-Jeong Kim  ;  Junhee Park  ;  Sun Kyoung Lee  ;  Ki Rim Kim  ;  Kwang-Kyun Park  ;  Won-Yoon Chung 
Citation
 Journal of Pathology, Vol.237(4) : 520-531, 2015 
Journal Title
 Journal of Pathology 
ISSN
 0022-3417 
Issue Date
2015
MeSH
Animals ; Biomarkers, Tumor/analysis* ; Blotting, Western ; Bone Neoplasms/secondary* ; Bone Resorption ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/secondary* ; Chemokine CCL19/biosynthesis ; Chemokine CCL5/biosynthesis ; Chemokine CXCL11/biosynthesis ; Core Binding Factor Alpha 3 Subunit/metabolism* ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Immunohistochemistry ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology* ; Mice ; Real-Time Polymerase Chain Reaction ; X-Ray Microtomography
Keywords
RANKL ; RUNX3 ; RUNX3-regulated chemokines ; cancer-mediated bone resorption ; non-small cell lung cancer ; osteoprotegerin
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.
Files in This Item:
T201504542.pdf Download
DOI
10.1002/path.4597
Appears in Collections:
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyun-Jeong(김현정) ORCID logo https://orcid.org/0000-0003-4608-2120
Park, Kwang Kyun(박광균)
Park, Jun Hee(박준희)
Lee, Sun Kyoung(이선경) ORCID logo https://orcid.org/0000-0002-3707-8050
Chung, Won Yoon(정원윤) ORCID logo https://orcid.org/0000-0001-8428-9005
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156784
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