Hematology/Oncology Division, Vanderbilt Medical Center, Nashville, TN, USA.
Mol Cancer. 2009 Oct 24;8:91. doi: 10.1186/1476-4598-8-91.
FUS1/TUSC2 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We previously showed that Tusc2-deficient mice display a complex immuno-inflammatory phenotype with a predisposition to cancer. The goal of this study was to analyze possible involvement of TUSC2 in malignant pleural mesothelioma (MPM) - an aggressive inflammatory cancer associated with exposure to asbestos.
TUSC2 insufficiency in clinical specimens of MPM was assessed via RT-PCR (mRNA level), Representational Oligonucleotide Microarray Analysis (DNA level), and immunohistochemical evaluation (protein level). A possible link between TUSC2 expression and exposure to asbestos was studied using asbestos-treated mesothelial cells and ROS (reactive oxygen species) scavengers. Transcripional effects of TUSC2 in MPM were assessed through expression array analysis of TUSC2-transfected MPM cells.
Expression of TUSC2 was downregulated in approximately 84% of MM specimens while loss of TUSC2-containing 3p21.3 region observed in approximately 36% of MPMs including stage 1 tumors. Exposure to asbestos led to a transcriptional suppression of TUSC2, which we found to be ROS-dependent. Expression array studies showed that TUSC2 activates transcription of multiple genes with tumor suppressor properties and down-regulates pro-tumorigenic genes, thus supporting its role as a tumor suppressor. In agreement with our knockout model, TUSC2 up-regulated IL-15 and also modulated more than 40 other genes (approximately 20% of total TUSC2-affected genes) associated with immune system. Among these genes, we identified CD24 and CD274, key immunoreceptors that regulate immunogenic T and B cells and play important roles in systemic autoimmune diseases. Finally, clinical significance of TUSC2 transcriptional effects was validated on the expression array data produced previously on clinical specimens of MPM. In this analysis, 42 TUSC2 targets proved to be concordantly modulated in MM serving as disease discriminators.
Our data support immuno-therapeutic potential of TUSC2, define its targets, and underscore its importance as a transcriptional stimulator of anti-tumorigenic pathways.
FUS1/TUSC2 是一种位于关键的 3p21.3 染色体区域的新型肿瘤抑制因子，该区域在多种癌症中经常缺失。我们之前的研究表明，Tusc2 缺陷的小鼠表现出复杂的免疫炎症表型，易患癌症。本研究的目的是分析 TUSC2 基因缺失在恶性胸膜间皮瘤（MPM）中的作用，MPM 是一种与石棉暴露相关的侵袭性炎症性癌症。
通过 RT-PCR（mRNA 水平）、代表性寡核苷酸微阵列分析（DNA 水平）和免疫组织化学评估（蛋白质水平）评估 MPM 临床标本中 TUSC2 的不足。使用经石棉处理的间皮细胞和 ROS（活性氧）清除剂研究 TUSC2 表达与暴露于石棉之间的可能联系。通过转染 TUSC2 的 MPM 细胞的表达谱分析评估 TUSC2 在 MPM 中的转录效应。
TUSC2 的表达在大约 84%的 MM 标本中下调，而在包括 1 期肿瘤在内的大约 36%的 MPM 中观察到 TUSC2 缺失 3p21.3 区域。暴露于石棉导致 TUSC2 的转录抑制，我们发现这是 ROS 依赖性的。表达谱研究表明，TUSC2 激活具有肿瘤抑制特性的多个基因的转录，并下调促肿瘤基因，从而支持其作为肿瘤抑制因子的作用。与我们的敲除模型一致，TUSC2 上调了 IL-15，并调节了 40 多个其他基因（约占 TUSC2 影响基因的 20%），这些基因与免疫系统有关。在这些基因中，我们鉴定出 CD24 和 CD274，它们是调节免疫原性 T 和 B 细胞的关键免疫受体，在系统性自身免疫性疾病中发挥重要作用。最后，我们在先前对 MPM 临床标本进行的表达谱分析中验证了 TUSC2 转录效应的临床意义。在这项分析中，42 个 TUSC2 靶点在 MM 中被证明是一致调节的，作为疾病的鉴别指标。
我们的数据支持 TUSC2 的免疫治疗潜力，确定了其靶点，并强调了它作为抗肿瘤途径转录刺激因子的重要性。
