Upregulation of MMP-2 by HMGA1 promotes transformation in undifferentiated, large-cell lung cancer.
Upregulation of MMP-2 by HMGA1 promotes transformation in undifferentiated, large-cell lung cancer.
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DOI：
10.1158/1541-7786.mcr-08-0336
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Resar LM
中科院分区：
文献类型：
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作者：
Hillion J;Wood LJ;Mukherjee M;Bhattacharya R;Di Cello F;Kowalski J;Elbahloul O;Segal J;Poirier J;Rudin CM;Dhara S;Belton A;Joseph B;Zucker S;Resar LM
尽管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尚不完全清楚。在这里，我们证明了HMGA1是一个重要的癌基因，在未分化的大细胞癌中驱动转化。首先，我们发现HMGA1基因在肺癌细胞系和原发人类肺癌中过表达。强制过表达HMGA1诱导来自正常组织的培养的肺细胞发生转化表型，细胞生长不依赖于锚定。相反，抑制HMGA1的表达阻止了H1299转移性、未分化的大细胞肺癌细胞中非锚定细胞的生长。我们还证明了基质金属蛋白酶-2(MMP2)基因是HMGA1上调大细胞癌细胞表达的下游靶点。在染色质免疫沉淀实验中，HMGA1在大细胞肺癌细胞中直接与基质金属蛋白酶-2启动子结合，而在鳞状细胞癌细胞中不结合。在大细胞癌细胞系中，HMGA1与基质金属蛋白酶-2的表达呈显著正相关。此外，干扰MMP2的表达阻断了H1299大细胞癌细胞的非锚定生长，表明HMGA1-MMP2通路是这些细胞这种转化表型所必需的。阻断基质金属蛋白酶-2的表达也抑制了H1299大细胞癌细胞的迁移和侵袭。我们的研究结果表明，基质金属蛋白酶-2在HMGA1介导的大细胞、未分化肺癌的转化中起重要作用，并支持在选定的肿瘤中针对这一途径的策略的发展。
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 demonstrate 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 demonstrate that the matrix metalloproteinase-2 (MMP-2) gene is a downstream target up-regulated 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.