Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis
Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis
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DOI：
10.1158/0008-5472.can-06-3950
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Mauviel, Alain
中科院分区：
文献类型：
--
作者：
Javelaud, Delphine;Mohammad, Khalid S.;Mauviel, Alain
黑色素瘤有转移到骨的倾向，在那里它暴露于高浓度的转化生长因子-β（TGF-β）。由于TGF-β促进其他实体瘤（如乳腺癌）的骨转移，我们测试了TGF-β在黑色素瘤骨转移中的作用。在骨转移的实验模型中研究了1205 Lu黑素瘤细胞，该细胞稳定转染以过表达天然TGF-β/Smad信号传导抑制剂Smad 7，其中将肿瘤细胞接种到裸鼠的左心室中。所有携带亲本和模拟转染的1205 Lu细胞的小鼠在肿瘤接种后5周发生溶骨性骨转移。与亲本和模拟转染的1205 Lu小鼠相比，携带1205 Lu-Smad 7肿瘤的小鼠在X线照片上具有显著更少的骨质溶解和更长的生存期。为了确定在携带1205 Lu-Smad 7克隆的小鼠中观察到的骨转移减少是否是由于已知增强乳腺癌细胞骨转移的TGF-β靶基因表达减少，我们分析了溶骨因子、甲状旁腺相关蛋白（PTHrP）和白细胞介素-11（IL-11）、趋化受体CXCR 4和骨桥蛋白在1205 Lu细胞中的基因表达。定量逆转录-PCR分析表明，PTHrP，IL-11，CXCR 4和骨桥蛋白mRNA稳态水平在对TGF-β的反应中显著增加，Smad 7和T β RI小分子抑制剂SB 431542阻止了这种诱导。此外，1205 Lu-Smad 7骨转移表达显著较低水平的IL-11、结缔组织生长因子和PTHrP。这些数据表明，TGF-β促进溶骨性骨转移，由于黑色素瘤通过刺激的促转移因子的表达，通过Smad途径。阻断TGF-β信号传导可能是黑色素瘤骨转移的有效治疗方法。
Melanoma has a propensity to metastasize to bone, where it is exposed to high concentrations of transforming growth factor-beta (TGF-beta). Because TGF-beta promotes bone metastases from other solid tumors, such as breast cancer, we tested the role of TGF-beta in melanoma metastases to bone. 1205Lu melanoma cells, stably transfected to overexpress the natural TGF-beta/Smad signaling inhibitor Smad7, were studied in an experimental model of bone metastasis whereby tumor cells are inoculated into the left cardiac ventricle of nude mice. All mice bearing parental and mock-transfected 1205Lu cells developed osteolytic bone metastases 5 weeks post-tumor inoculation. Mice bearing 1205Lu-Smad7 tumors had significantly less osteolysis on radiographs and longer survival compared with parental and mock-transfected 1205Lu mice. To determine if the reduced bone metastases observed in mice bearing 1205Lu-Smad7 clones was due to reduced expression of TGF-beta target genes known to enhance metastases to bone from breast cancer cells, we analyzed gene expression of osteolytic factors, parathyroid hormone-related protein (PTHrP) and interleukin-11 (IL-11), the chemotactic receptor CXCR4, and osteopontin in 1205Lu cells. Quantitative reverse transcription-PCR analysis indicated that PTHrP, IL-11, CXCR4, and osteopontin mRNA steady-state levels were robustly increased in response to TGF-beta and that Smad7 and the T beta RI small-molecule inhibitor, SB431542, prevented such induction. In addition, 1205Lu-Smad7 bone metastases expressed significantly lower levels of IL-11, connective tissue growth factor, and PTHrP. These data suggest that TGF-beta promotes osteolytic bone metastases due to melanoma by stimulating the expression of prometastatic factors via the Smad pathway. Blockade of TGF-beta signaling may be an effective treatment for melanoma metastasis to bone.