Abstract 1414: The role of RUNX3 and RUNX3-related chemokines in lung cancer-induced bone resorption.

Abstract

Abstract Lung cancer frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. Runt-related transcription factor 3 (RUNX3) functions as a tumor suppressor in many cancers, and may be also important in the development of lung cancer. In this study, we found that RUNX3 knockdown increased the proliferation, migration and invasion of human lung cancer A549 cells. Interestingly, the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic hFOB1.19 cells treated with RUNX3 knockdown A549 cell-derived conditioned medium (CM) as compared to CM of RUNX3-expressing A549 cells. In the chemokine and receptor PCR array to identify RUNX3-regulated factors that mediate bone invasion of lung cancer cells, RUNX3 knockdown led to upregulation of CCL5 and downregulation of CCL19 and CXCL11 in A549 cells. CCL5 increased the proliferation, migration and invasion of A549 cells but CCL19 and CXCL11 had not a remarkable effect. CCL5 increased RANKL/OPG ratio in hFOB1.19 cells but CCL19 and CXCL11 decreased. CCL5 promoted RANKL-induced osteoclast differentiation in BMMs, while CCL19 and CXCL11 reduced. In the mouse model that RUNX3-expressing or RUNX3 knockdown A549 cells were injected subcutaneously over the calvaria, RUNX3 knockdown resulted in the increased tumor size and severe bone destruction. Additionally, in the osteolytic bone invasion model that the cells were inoculated into bone marrow of mouse tibia, bone lesions appeared more seriously in mice injected with RUNX3 knockdown A549 cells. The serum level of CCL5 was increased, while those of CCL19 and CXCL11 were decreased, in RUNX3 knockdown A549 cell-inoculated mice as compared with RUNX3-expressing A549 cell-inoculated mice. Taken together, bone invasion of lung cancer cells may be closely related with RUNX3 and RUNX3-regulated chemokines. Citation Format: Hyun-Jeong Kim, Won-Yoon Chung, Kwang-Kyun Park. The role of RUNX3 and RUNX3-related chemokines in lung cancer-induced bone resorption. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1414. doi:10.1158/1538-7445.AM2013-1414