Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA.
Clin Colorectal Cancer. 2011 Sep;10(3):188-93. doi: 10.1016/j.clcc.2011.03.014. Epub 2011 Apr 28.
The antiapoptotic protein survivin has been demonstrated to play an important role in colorectal carcinogenesis. However it is unclear whether the upregulation of survivin is maintained through progressive stages of disease, or if other apoptosis-related genes are coexpressed and/or repressed. We sought to evaluate survivin expression in colonic neoplasia and identify relationships with additional regulators of apoptosis.
Tissue samples from 168 patients with primary colorectal cancer were profiled using the GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix, Santa Clara, CA) and evaluated for survivin expression. Immunohistochemical staining for survivin and a panel of apoptosis-associated proteins were used in 86 patients with tissue microarray (TMA) blocks; scoring was by stain intensity and percentage of positive cells (range, 0-9).
Survivin mRNA was upregulated (1.8-fold increase) in primary colon cancers- irrespective of American Joint Committee on Cancer (AJCC) stage- and metastases compared with normal colonic tissue (P < .0001). Survivin staining was positive in 93% of adenocarcinomas (median immunohistochemistry [IHC] score: 2 [range, 1-6]), 100% of adenomas (1 [range,1-2]), and 43% of normal colonic mucosa (1, [range 1-2]) (P = .006). Survivin expression increased with worsening tumor grade (P < .05). In colon cancers, survivin expression positively correlated with the coexpression of PUMA (P < .001), TACE (P = .003), and MCL1 (P = .01), and trended toward an inverse correlation with BAX (P = .058).
Survivin expression increases during the normal mucosa-adenoma-carcinoma sequence and is maintained throughout progression of disease, which strengthens its appeal as a therapeutic target. Furthermore, we have demonstrated co-overexpression of several other apoptosis-related genes, which may in turn serve as additional and potentially synergistic therapeutic targets.
抗凋亡蛋白 survivin 已被证明在结直肠癌发生中发挥重要作用。然而，目前尚不清楚 survivin 的上调是否是通过疾病的进行性阶段维持的，或者是否有其他凋亡相关基因共同表达和/或受到抑制。我们试图评估 survivin 在结直肠肿瘤中的表达，并确定与其他凋亡调节因子的关系。
对 168 例原发性结直肠癌患者的组织样本进行了分析，使用 GeneChip Human Genome U133 Plus 2.0 阵列（Affymetrix，Santa Clara，CA）进行分析，并评估了 survivin 的表达。对 86 例组织微阵列（TMA）块中的 survivin 和一组凋亡相关蛋白进行了免疫组织化学染色；评分依据染色强度和阳性细胞百分比（范围为 0-9）。
与正常结肠组织相比，原发性结肠癌-无论美国癌症联合委员会（AJCC）分期如何-和转移灶中的 survivin mRNA 均上调（增加 1.8 倍）（P <.0001）。在腺癌中，survivin 染色阳性率为 93%（中位数免疫组化[IHC]评分：2 [范围 1-6]），在腺瘤中为 100%（1 [范围 1-2]），在正常结肠黏膜中为 43%（1 [范围 1-2]）（P =.006）。survivin 表达随着肿瘤分级的恶化而增加（P <.05）。在结肠癌中，survivin 表达与 PUMA（P <.001）、TACE（P =.003）和 MCL1（P =.01）的共表达呈正相关，与 BAX 的表达呈负相关趋势（P =.058）。
survivin 的表达在正常黏膜-腺瘤-癌序列中增加，并在疾病进展过程中持续维持，这使其作为治疗靶点的吸引力更强。此外，我们已经证明了其他几个凋亡相关基因的共表达，这可能反过来成为额外的、潜在协同的治疗靶点。
