Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Cancer Res. 2009 Nov;7(11):1803-12. doi: 10.1158/1541-7786.MCR-08-0336. Epub 2009 Nov 10.
Although lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we show that HMGA1 is an important oncogene that drives transformation in undifferentiated, large-cell carcinoma. First, we show that the HMGA1 gene is overexpressed in lung cancer cell lines and primary human lung tumors. Forced overexpression of HMGA1 induces a transformed phenotype with anchorage-independent cell growth in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA1 expression blocks anchorage-independent cell growth in the H1299 metastatic, undifferentiated, large-cell human lung carcinoma cells. We also show that the matrix metalloproteinase-2 (MMP-2) gene is a downstream target upregulated by HMGA1 in large-cell carcinoma cells. In chromatin immunoprecipitation experiments, HMGA1 binds directly to the MMP-2 promoter in vivo in large-cell lung cancer cells, but not in squamous cell carcinoma cells. In large-cell carcinoma cell lines, there is a significant, positive correlation between HMGA1 and MMP-2 mRNA. Moreover, interfering with MMP-2 expression blocks anchorage-independent cell growth in H1299 large-cell carcinoma cells, indicating that the HMGA1-MMP-2 pathway is required for this transformation phenotype in these cells. Blocking MMP-2 expression also inhibits migration and invasion in the H1299 large-cell carcinoma cells. Our findings suggest an important role for MMP-2 in transformation mediated by HMGA1 in large-cell, undifferentiated lung carcinoma and support the development of strategies to target this pathway in selected tumors.
虽然肺癌是全球癌症死亡的主要原因，但导致肺癌的确切分子机制仍不完全清楚。在这里，我们表明 HMGA1 是一种重要的癌基因，它驱动未分化的大细胞癌的转化。首先，我们表明 HMGA1 基因在肺癌细胞系和原发性人肺肿瘤中过度表达。HMGA1 的强制过表达诱导培养的来源于正常组织的肺细胞中的转化表型，具有无锚定依赖性细胞生长。相反，抑制 HMGA1 表达可阻止转移性、未分化、大细胞人肺癌细胞 H1299 中的无锚定依赖性细胞生长。我们还表明，基质金属蛋白酶-2（MMP-2）基因是 HMGA1 在大细胞癌细胞中上调的下游靶标。在染色质免疫沉淀实验中，HMGA1 在体内直接结合大细胞肺癌细胞中的 MMP-2 启动子，但不在鳞状细胞癌细胞中结合。在大细胞癌细胞系中，HMGA1 和 MMP-2 mRNA 之间存在显著的正相关。此外，干扰 MMP-2 表达可阻止 H1299 大细胞癌细胞的无锚定依赖性细胞生长，表明 HMGA1-MMP-2 通路是这些细胞中这种转化表型所必需的。阻断 MMP-2 表达也抑制了 H1299 大细胞癌细胞的迁移和侵袭。我们的研究结果表明，MMP-2 在 HMGA1 介导的未分化大细胞肺癌的转化中起重要作用，并支持针对该通路在选定肿瘤中发展策略的研究。
