Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression
Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression
复制标题
乳腺癌细胞中骨形态发生蛋白 1a 型受体 (BMPR1a) 的敲低可通过抑制 RANKL 表达来保护骨骼免受乳腺癌诱导的骨溶解。
DOI：
10.1159/000487784
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Wang, Yang
中科院分区：
文献类型：
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作者：
Liu, Yang;Zhang, Ran-Xi;Wang, Yang
背景/目的：骨形态发生蛋白（BM Ps）和BMP受体广泛参与乳腺癌的溶骨转移，但它们在肿瘤-基质相互作用中的作用很大程度上未知。在这项研究中，我们研究了 BMP 受体 1a 型 (BMPR1a) 是否可以改变转移性癌细胞和破骨细胞前体之间的相互作用。方法：利用腺病毒介导的RNA干扰干扰人乳腺癌细胞系的靶基因，并将癌细胞注射到裸鼠胫骨内。通过生物发光成像和 microCT 检查荷瘤小鼠。通过一系列染色方法测量转移腿的切片。将小鼠骨髓单个核细胞或RAW264.7细胞与乳腺癌细胞条件培养基一起培养。逆转录聚合酶链反应。采用Western blotting和ELISA检测靶分子的mRNA和蛋白表达。结果：肿瘤-骨界面处的MDA-MB-231-luc细胞的BMPRla表达明显强于远离界面的癌细胞。与对照组相比，注射 BMPR1a 敲低 MDAMB-231-luc 细胞的小鼠显示肿瘤生长和骨破坏减少。 MDA-MB-231-luc 细胞或 MCF-7 细胞的 BMPRla 敲低 (KD) 降低了 NF-κ B 配体 (RANKL) 受体激活剂的水平。 p38 抑制剂降低 MDA-MB-231-luc 细胞或 MCF-7 细胞中的 RANKL 水平。与对照组相比，乳腺癌细胞p38的敲除减少了癌症诱导的破骨细胞生成。结论：敲低乳腺癌细胞的 BMPRla 可通过 p38 途径抑制其 RANKL 的产生，并抑制癌症诱导的破骨细胞生成，这表明 BMPRla 可能是乳腺癌诱导的溶骨转移的可能靶点。 (C) 2018 年作者由巴塞尔 S. Karger AG 出版。
Background/Aims: Bone morphogenetic proteins (BM Ps) and BM P receptors widely participate in osteolytic metastasis of breast cancer, while their role in tumor-stromal interaction is largely unknown. In this study, we investigated whether BMP receptor type la (BMPR1a) can alter the interaction between metastatic cancer cells and osteoclast precursors. Methods: Adenovirusmediated RNA interference was used to interrupt target genes of human breast cancer cell lines and nude mice were injected intratibially with the cancer cells. Tumor-bearing mice were examined by bioluminescence imaging and microCT. Sections of metastatic legs were measured by a series of staining methods. Murine bone marrow mononuclear cells or RAW264.7 cells were cultured with conditioned media of breast cancer cells. RT-PCR. Western blotting and ELISA were used to test mRNA and protein expressions of target molecules. Results: Expression of BMPRla of MDA-MB-231-luc cells at tumor-bone interface was apparently stronger than that of cancer cells distant from the interface. Mice injected with BMPR1a-knockdown MDAMB-231-luc cells showed reduced tumor growth and bone destruction compared with control groups. Knockdown (KD) of BMPRla of MDA-MB-231-luc cells or MCF-7 cells decreased the level of receptor activator for NF-kappa B ligand (RANKL). Level of RANKL in MDA-MB-231-luc cells or MCF-7 cells was reduced by p38 inhibitor. Compared with control group, knockdown of p38 of breast cancer cells decreased cancer-induced osteoclastogenesis. Conclusion: Knockdown of BMPRla of breast cancer cells suppresses their production of RANKL via p38 pathway and inhibits cancer-induced osteoclastogenesis, which indicates that BMPRla might be a possible target in breast cancer-induced osteolytic metastasis. (C) 2018 The Au thor(s) Published by S. Karger AG, Basel.