The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells
The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells
复制标题
DOI：
10.1093/carcin/bgg100
复制
发表时间：
2003-09-01
期刊：
影响因子：
4.7
通讯作者：
Langenfeld, J
中科院分区：
文献类型：
--
作者：
Langenfeld, EM;Calvano, SE;Langenfeld, J
为了帮助识别可能调节肺癌转移的基因，我们在患者来源的非小细胞肺癌（NSCLC）和永生化的正常人支气管上皮细胞之间进行了代表性差异分析。结果显示骨形态发生蛋白-2/4（BMP）mRNA在肺癌组织中有表达。已知BMP-2/4在胚胎发育期间诱导多能细胞分化、增强细胞迁移和刺激增殖。尽管BMP-2/4是强有力的形态发生剂，但尚不清楚BMP-2/4在人类癌中是否具有显著的生物活性。此外，尚未确定成熟的活性BMP-2/4蛋白是否在患者来源的肿瘤中异常表达。本研究的目的是确定成熟BMP-2/4蛋白的表达是否在人肺癌中失调，并确定其是否具有不良的生物学活性。这项研究表明，成熟的BMP-2蛋白，而不是BMP-4，是高度过度表达在人类NCSLC中，很少或没有表达在正常肺组织或良性肺肿瘤。BMP-2的表达定位于癌细胞。重组BMP-2体外刺激人肺癌细胞株A549和H7249的迁移和侵袭能力在体内，重组BMP-2促进了裸鼠皮下注射A549细胞形成的肿瘤的生长。此外，用重组头蛋白或抗BMP-2抗体抑制BMP-2活性导致肿瘤生长显著减少。这项研究表明，成熟的BMP-2蛋白的表达失调，在大多数非小细胞肺癌。BMP-2能促进肿瘤细胞的迁移和侵袭，并在体内刺激肿瘤生长，这表明它在肺癌中具有重要的生物学活性。
To help identify genes, which may regulate metastasis in lung cancer, we performed representational difference analysis between a patient-derived non-small cell lung carcinoma (NSCLC) and immortalized normal human bronchial epithelial cells. This analysis revealed that bone morphogenetic proteins-2/4 (BMP) mRNA was expressed in the lung carcinoma. BMP-2/4 are known to induce pluripotent cell differentiation, enhance cell migration and stimulate proliferation during embryonic development. Despite being powerful morphogens it is not known whether BMP-2/4 have significant biological activity in human carcinomas. Furthermore, it has not been established whether the mature active BMP-2/4 protein is aberrantly expressed in patient-derived tumors. The purpose of this study was to determine whether the expression of the mature BMP-2/4 protein is disregulated in human lung carcinomas and to establish whether it has adverse biological activity. This study reveals that the mature BMP-2 protein, but not BMP-4, is highly over-expressed in human NCSLC with little to no expression in normal lung tissue or benign lung tumors. The expression of BMP-2 localized specifically to the cancer cells. Recombinant BMP-2 stimulated in vitro, the migration and invasiveness of the A549 and H7249 human lung cancer cell lines. In vivo, recombinant BMP-2 enhanced the growth of tumors formed from A549 cells injected subcutaneously into nude mice. Furthermore, inhibition of BMP-2 activity with either recombinant noggin or anti-BMP-2 antibody resulted in a significant reduction in tumor growth. This study shows that expression of the mature BMP-2 protein is disregulated in the majority of NSCLC. BMP-2 enhancement of tumor cell migration and invasion, as well as stimulating tumor growth in vivo, suggests it has important biological activity in lung carcinomas.