IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis
IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis
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IL-11 通过不依赖 RANKL 的破骨细胞生成促进乳腺癌骨转移中的骨质溶解至关重要
DOI：
10.1038/s41419-019-1594-1
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发表时间：
2019-04-30
影响因子：
9
通讯作者：
Dong, Shiwu
中科院分区：
文献类型：
--
作者：
Liang, Mengmeng;Ma, Qinyu;Dong, Shiwu
已从乳腺癌细胞中鉴定出多种导致骨溶解的溶骨因子，但在恶性溶骨循环之前，关于哪种因子在启动过程中起重要作用的知之甚少。在此，我们提出了体外和体内证据，以阐明白细胞介素11(IL-11)在乳腺癌骨转移介导的骨溶解中的重要作用。动物实验表明，在BALB/c-nu/nu裸鼠中，骨转移性BoM-1833细胞较MCF7细胞和亲代MDA-MB-231细胞诱导更早的骨溶解和更快的肿瘤生长。IL-11被进一步筛选和鉴定为BOM-1833细胞不依赖核因子受体激活剂κB配体(RANKL)诱导破骨细胞分化所必需的分泌因子。机制研究表明，JAK1/STAT3信号通路作为IL-11、STAT3激活的下游效应因子，进一步诱导了破骨细胞发生所必需的c-Myc的表达。通过抑制STAT3的磷酸化，AG-490被证明有效地减少了转移窝骨溶解和肿瘤生长。总之，我们的结果揭示了IL-11在乳腺癌骨转移介导的骨溶解中的重要作用和潜在的分子机制。通过AG-490靶向STAT3是一种潜在的减轻骨转移乳腺癌骨溶解和肿瘤生长的治疗策略。
A variety of osteolytic factors have been identified from breast cancer cells leading to osteolysis, but less is known about which factor plays an essential role in the initiation process prior to the overt vicious osteolytic cycle. Here, we present in vitro and in vivo evidences to clarify the role of interleukin-11 (IL-11) as an essential contributor to breast cancer bone metastasis mediated osteolysis. Animal studies showed that bone specific metastatic BoM-1833 cells induce earlier onset of osteolysis and faster tumor growth compared with MCF7 and parental MDA-MB-231 cells in BALB/c-nu/nu nude mice. IL-11 was further screened and identified as the indispensable factor secreted by BoM-1833 cells inducing osteoclastogenesis independently of receptor activator of nuclear factor κB ligand (RANKL). Mechanistic investigation revealed that the JAK1/STAT3 signaling pathway as a downstream effector of IL-11, STAT3 activation further induces the expression of c-Myc, a necessary factor required for osteoclastogenesis. By inhibiting STAT3 phosphorylation, AG-490 was shown effective in reducing osteolysis and tumor growth in the metastatic niche. Overall, our results revealed the essential role and the underlying molecular mechanism of IL-11 in breast cancer bone metastasis mediated osteolysis. STAT3 targeting through AG-490 is a potential therapeutic strategy for mitigating osteolysis and tumor growth of bone metastatic breast cancer.