Transcriptional profiles of TIMP-2 and Ala+TIMP-2 A549 overexpressing cells and in tumor xenografts.

TIMP-2 is an endogenous angiogenesis inhibitor, i.e. inhibits endothelial cell proliferation and tumor angiogenesis. As a result, TIMP-2 inhibits tumor growth and progression to metastasis. Understanding, therefore, the mechanisms of TIMP-2-mediated tumor growth inhibition would provide further support on the use of TIMP-2 as a novel biological agent for cancer therapy. We used microarray analysis to determine the TIMP-2 and Ala+TIMP-2 transcriptional profiles of A549 cancer cells in order to understand how TIMP-2 inhibits tumor growth and angiogenesis. We overexpressed TIMP-2 and its mutant (does not inhibit MMP) in A549 human lung cancer cells and determined TIMP-2 and Ala+TIMP-2 transcriptional profiles, groups of genes and associated biological functions. We then injected the cells in NOD-SCID mice and RNA from tumors were isolated for further analysis to identify genes that are associated with tumor growth inhibition.

TIMP-2是一种内源性血管生成抑制剂，可通过抑制内皮细胞增殖与肿瘤血管生成阻断肿瘤生长及转移进程。因此，阐明TIMP-2介导的肿瘤生长抑制机制，可为将TIMP-2开发为新型癌症治疗生物制剂提供坚实的理论支撑。本研究采用微阵列分析技术，解析TIMP-2及Ala+TIMP-2在A549人肺癌细胞中的转录谱，以揭示TIMP-2抑制肿瘤生长与血管生成的分子机制。我们将TIMP-2及其不具备基质金属蛋白酶（Matrix Metalloproteinase, MMP）抑制活性的突变体在A549人肺癌细胞中过表达，进而检测TIMP-2与Ala+TIMP-2的转录谱、基因集及相关生物学功能。随后将上述转染细胞接种至NOD-SCID重症联合免疫缺陷小鼠体内，从肿瘤组织中分离RNA以开展后续分析，从而筛选出与肿瘤生长抑制相关的功能基因。