Gharib Tarek G, Chen Guoan, Huang Chian-Ching, Misek David E, Iannettoni Mark D, Hanash Samir M, Orringer Mark B, Beer David G
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
Clin Lung Cancer. 2004 Mar;5(5):307-12. doi: 10.3816/CLC.2004.n.011.
Vascular endothelial growth factor (VEGF) is regulated by the hypoxia-inducible factor 1 (HIF1) pathway and is implicated in tumor progression and patient survival in many types of cancer. Insulin-like growth factor-binding protein 3 (IGFBP3) is also regulated by HIF1 but works in a completely different manner by modulating the activities of insulin-like growth factors and inducing apoptosis. In this study, 2-dimensional (2D) polyacrylamide gel electrophoresis (PAGE) was used to analyze the protein expression profiles of VEGF and IGFBP3 isoforms in 93 lung adenocarcinomas and 10 uninvolved lung samples. The same samples were examined for messenger RNA (mRNA) expression with use of oligonucleotide arrays. Correlation analysis in the lung adenocarcinomas between mRNA expression levels of VEGF and all 4966 other genes was used to identify other biologic processes that may be associated with increased VEGF expression. Two-dimensional gel separations revealed 7 VEGF protein isoforms and 5 isoforms of IGFBP3. VEGF and IGFBP3 mRNA were found to be overexpressed in bronchial-derived lung adenocarcinomas (P < 0.0001), and expression was decreased in well-differentiated lung adenocarcinomas (P < 0.0002). There was a significant correlation (P < 0.01) between VEGF and IGFBP3 mRNA in lung adenocarcinomas; however, no correlation was detected in uninvolved lung samples. Forty genes were identified as the most significantly associated with VEGF expression (r > 0.38, P < 0.001), 17 of which were also associated with IGFBP3, and 12 were known to be induced through the HIF1 pathway. Among other highly correlated genes, several, including bradykinin receptor B2, suggest additional cellular processes that were not previously known to be associated with VEGF expression in lung adenocarcinoma.
血管内皮生长因子（VEGF）受缺氧诱导因子1（HIF1）途径调控，并与多种癌症的肿瘤进展和患者生存率相关。胰岛素样生长因子结合蛋白3（IGFBP3）也受HIF1调控，但通过调节胰岛素样生长因子的活性和诱导细胞凋亡以完全不同的方式发挥作用。在本研究中，二维（2D）聚丙烯酰胺凝胶电泳（PAGE）用于分析93例肺腺癌和10例未受累肺组织样本中VEGF和IGFBP3亚型的蛋白质表达谱。使用寡核苷酸阵列检测相同样本中的信使核糖核酸（mRNA）表达。通过对肺腺癌中VEGF mRNA表达水平与其他所有4966个基因进行相关性分析，以确定可能与VEGF表达增加相关的其他生物学过程。二维凝胶分离显示7种VEGF蛋白亚型和5种IGFBP3亚型。发现VEGF和IGFBP3 mRNA在支气管源性肺腺癌中过表达（P < 0.0001），而在高分化肺腺癌中表达降低（P < 0.0002）。肺腺癌中VEGF和IGFBP3 mRNA之间存在显著相关性（P < 0.01）；然而，在未受累肺组织样本中未检测到相关性。40个基因被确定为与VEGF表达最显著相关（r > 0.38，P < 0.001），其中17个基因也与IGFBP3相关，12个基因已知通过HIF1途径诱导。在其他高度相关的基因中，包括缓激肽受体B2在内的几个基因提示了以前未知与肺腺癌中VEGF表达相关的其他细胞过程。
