Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Lung Cancer. 2010 Dec;70(3):253-62. doi: 10.1016/j.lungcan.2010.02.012. Epub 2010 Mar 24.
The RBM5/H37 gene is located at the most 'sought-after' tumor suppressor locus in lung cancer, 3p21.3. This region of most frequent chromosomal deletion found at the earliest stage in lung cancer development houses 19 genes, many of which may act together as a 'tumor suppressor group', representing one of the most promising opportunities for development of new diagnostics/prognostics and therapeutics for lung cancer as well as for many other types of cancers. For the past decade, we have demonstrated tumor suppressor function of RBM5 in vitro and in vivo involving cell cycle arrest and apoptosis, as well as loss of RBM5 mRNA and protein expression in primary lung tumors. Here we report our latest data suggesting that RBM5 may regulate inhibition of metastasis in lung cancer. We performed cDNA microarray to identify global gene expression changes caused by RBM5 gene knockdown. In order to identify "consensus" pathways consistently deregulated by RBM5 loss irrespective of genetic background, the experiments were repeated in three different lung cancer cell lines of varying RBM5 expression levels, a normal lung epithelial cell line, and a normal breast epithelial cell line. Both Gene Set Enrichment Analysis (GSEA) and individual gene analysis identified consistent, statistically significant gene expression changes common to all five cell pairs examined. Genes involved in the functions of cell adhesion, migration and motility, known to be important in the metastatic process, were upregulated with RBM5-knockdown. These genes include Rac1, β-catenin, collagen, laminin and the overall gene set of the gene ontology group "proteinaceous extracellular matrix". Among these, we have focused on Rac1 and β-catenin which play essential roles in cell movement downstream of Wnt signaling. We have confirmed increased protein expression of β-catenin and increased protein activation of Rac1 with RBM5-knockdown. In addition, we found that RBM5 protein expression loss in primary lung tumors is correlated with increased lymph node metastasis in a small number of lung cancer patients. These data are corroborated by an independent report showing RBM5 as part of a 17-gene signature of metastasis in primary solid tumors. Taken together, the accumulated evidence suggests that RBM5 expression loss may increase the metastatic potential of tumors. Further study is warranted to evaluate the potential clinical utility of RBM5 in lung cancer diagnostics, prognostics and therapeutics.
RBM5/H37 基因位于肺癌中最“抢手”的肿瘤抑制基因座 3p21.3。在肺癌发展的最早阶段发现的这个染色体缺失最频繁的区域，有 19 个基因，其中许多基因可能作为一个“肿瘤抑制基因群”共同作用，这是开发肺癌以及许多其他类型癌症的新诊断/预后和治疗方法最有希望的机会之一。在过去的十年中，我们已经在体外和体内证明了 RBM5 的肿瘤抑制功能，涉及细胞周期停滞和细胞凋亡，以及原发性肺癌肿瘤中 RBM5 mRNA 和蛋白质表达的丧失。在这里，我们报告了我们的最新数据，表明 RBM5 可能调节肺癌转移的抑制。我们进行了 cDNA 微阵列分析，以确定 RBM5 基因敲低引起的全局基因表达变化。为了确定无论遗传背景如何，RBM5 缺失一致下调的“共识”途径，我们在三种不同的肺癌细胞系（不同的 RBM5 表达水平）、正常肺上皮细胞系和正常乳腺上皮细胞系中重复了实验。基因集富集分析（GSEA）和单个基因分析都确定了所有五个细胞对检查中共同的一致的、具有统计学意义的基因表达变化。参与细胞粘附、迁移和运动功能的基因，已知在转移过程中很重要，随着 RBM5 敲低而上调。这些基因包括 Rac1、β-catenin、胶原蛋白、层粘连蛋白和基因本体组“蛋白质细胞外基质”的整体基因集。在这些基因中，我们重点关注 Rac1 和β-catenin，它们在 Wnt 信号下游的细胞运动中起关键作用。我们已经证实 RBM5 敲低后β-catenin 的蛋白质表达增加和 Rac1 的蛋白质激活增加。此外，我们发现原发性肺癌肿瘤中 RBM5 蛋白表达的丧失与一小部分肺癌患者中淋巴结转移的增加相关。这些数据得到了一份独立报告的证实，该报告显示 RBM5 是原发性实体肿瘤转移的 17 个基因特征的一部分。总之，累积的证据表明 RBM5 表达的丧失可能会增加肿瘤的转移潜力。需要进一步研究来评估 RBM5 在肺癌诊断、预后和治疗中的潜在临床应用价值。
