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. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasion

“…The effect of CCL28 on OSCC bone invasion was analyzed as previously described (26,27). The collected calvaria and tibiae were analyzed scanned with a micro-CT (μCT) system (SkyScan 1076).…”

“…We previously reported the distinct roles of RUNX3 expression in bone destruction caused by different types of cancer. RUNX3 inhibited lung cancer cell-mediated bone destruction and blocked cancer cell invasion and osteoclastogenesis by downregulating CCL5 and upregulating CCL19 and CXCL11 (26). In con-Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival.…”

Artemisinin-Daumone Hybrid Inhibits Cancer Cell-Mediated Osteolysis by Targeting Cancer Cells and Osteoclasts

“…RNA (2 μg) was then converted to cDNA using the RT profiler PCR array plate (PAHS-075ZA, Human Transcription Factor, Sabioscience). Quantitative real-time PCR and data analyses were conducted as previously described [24]. The mRNA expression of each gene was normalized to the expression of the following housekeeping genes: GAPDH, beta 2-microglobulin, hypoxanthine phosphoribosyl-transferase 1, ribosomal protein L13a, and beta-actin.…”

“…The A549 cell-injected mice (n = 5) were administered vehicle, ARTD (10 or 20 mg/kg), or gefitinib (10 mg/kg) by oral gavage 5 times per week. After 6 weeks, microcomputed tomography (μCT) analyses and histological examinations were performed as previously described, and bone metabolic markers in the sera were measured as previously described [24,25]. Twodimensional (2D) and 3D images were generated using NRecon software (SkyScan, Aartselaar, Belgium).…”

The interconnected role of chemokines and estrogen in bone metabolism

“…Numerous chemokines have been found to be involved in the process of bone metabolism (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49), as summarized in Table 2. OBs are derived from bone marrow mesenchymal stem cells (BMMSCs).…”