Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.
Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.
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DOI：
10.1002/path.4597
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Chung WY
中科院分区：
文献类型：
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作者：
Kim HJ;Park J;Lee SK;Kim KR;Park KK;Chung WY
非小细胞肺癌（NSCLC）经常转移到骨，这与显著的发病率和令人沮丧的预后相关。RUNX 3在肺癌中作为肿瘤抑制因子发挥作用，在浸润性肺腺癌中表达缺失的频率高于浸润前病变。在这里，我们表明RUNX 3和RUNX 3调节的趋化因子与NSCLC介导的骨吸收有关。值得注意的是，在用RUNX 3敲低NSCLC细胞衍生的条件培养基处理的人成骨细胞中，核因子-κB受体激活因子配体（RANKL）/骨保护素（OPG）比值（破骨细胞生成刺激的指标）显著增加。我们的目的是确定RUNX 3调节因子，改变成骨细胞RANKL/OPG比值，并发现RUNX 3敲低导致NSCLC细胞中CCL 5上调和CCL 19和CXCL 11下调。在接受RUNX 3敲低细胞的小鼠的颅骨和胫骨中，肿瘤大小显著增加，并诱导更严重的溶骨性病变。响应于RUNX 3敲低，CCL 5的血清和组织水平增加，而CCL 19和CXCL 11降低。此外，CCL 5以剂量依赖性方式增加肺癌细胞的增殖、迁移和侵袭;然而，CCL 19和CXCL 11没有显示出任何显著作用。成骨细胞中的RANKL/OPG比率被CCL 5增加，但被CCL 19和CXCL 11降低。在RANKL处理的骨髓巨噬细胞中，CCL 5促进破骨细胞分化，但CCL 19和CXCL 11减少破骨细胞生成。这些发现表明，RUNX 3和相关趋化因子是预测和/或治疗NSCLC诱导的骨破坏的有用标志物。版权所有© 2015作者.病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
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.