Institute of Pathology, University of Regensburg, Germany.
Exp Mol Pathol. 2012 Feb;92(1):74-81. doi: 10.1016/j.yexmp.2011.10.004. Epub 2011 Oct 15.
Several of the different bone morphogenetic proteins (BMPs) are involved in development and progression of specific tumors. For hepatocellular carcinoma (HCC) only BMP4 and BMP6 are described to be important for carcinogenesis. However, up to now neither the influence of other BMPs on tumor progression, nor the responsible signaling pathways to mediate target gene expression in HCC are known. In order to characterize BMP expression pattern in HCC cell lines, we performed RT-PCR analysis and revealed enhanced expression levels of several BMPs (BMP4, 6, 7, 8, 9, 10, 11, 13 and 15) in HCC. Thus, we treated HCC cells with the general BMP inhibitors chordin and noggin to determine the functional relevance of BMP overexpression and observed decreased migration and invasion of HCC cells. A cDNA microarray of noggin treated HCC cells was performed to analyze downstream targets of BMPs mediating these oncogenic functions. Subsequent analysis identified collagen XVI as 'Smad signaling specific' and nidogen-2 as 'MAPK/ERK signaling specific' BMP-target genes. To examine which signaling pathway is mainly responsible for the oncogenic role of BMPs in HCC, we treated HCC cells with dorsomorphin to determine the influence of BMP activated Smad signaling. Interestingly, also migratory and invasive behavior of dorsomorphin treated HCC cells was diminished. In summary, our findings demonstrate enhanced expression levels of several BMPs in HCC supporting enhanced migratory and invasive phenotype of HCC cells mainly via activation of Smad signaling.
几种不同的骨形态发生蛋白（BMPs）参与特定肿瘤的发生和进展。对于肝细胞癌（HCC），只有 BMP4 和 BMP6 被描述为与癌发生有关。然而，到目前为止，其他 BMPs 对肿瘤进展的影响，以及介导 HCC 中靶基因表达的负责信号通路都尚不清楚。为了描述 HCC 细胞系中 BMP 的表达模式，我们进行了 RT-PCR 分析，发现几种 BMP（BMP4、6、7、8、9、10、11、13 和 15）在 HCC 中的表达水平增强。因此，我们用通用的 BMP 抑制剂 chordin 和 noggin 处理 HCC 细胞，以确定 BMP 过表达的功能相关性，并观察到 HCC 细胞的迁移和侵袭减少。对 noggin 处理的 HCC 细胞进行 cDNA 微阵列分析，以分析介导这些致癌功能的 BMP 下游靶基因。随后的分析确定胶原 XVI 为“Smad 信号特异性”，纤连蛋白-2 为“MAPK/ERK 信号特异性”BMP 靶基因。为了研究哪种信号通路主要负责 BMP 在 HCC 中的致癌作用，我们用 dorsomorphin 处理 HCC 细胞，以确定 BMP 激活的 Smad 信号的影响。有趣的是，dorsomorphin 处理的 HCC 细胞的迁移和侵袭行为也减少了。总之，我们的研究结果表明，HCC 中几种 BMPs 的表达水平增强，支持 HCC 细胞的迁移和侵袭表型增强，主要通过激活 Smad 信号。
