Pathology Division, Research Center for Innovative Oncology, Chiba 277-8577, Japan.
Int J Oncol. 2011 Feb;38(2):345-53. doi: 10.3892/ijo.2010.868. Epub 2010 Dec 9.
EZH2 and BMI1 are transcriptional repressors and have been implicated in the progression of human cancers. Squamous cell carcinoma of the esophagus (ESCC) is one of the most aggressive carcinomas in the gastrointestinal tract and generally has an unfavorable outcome. In the present study, we immunohistochemically investigated the expression of EZH2 and BMI1 in 136 surgically resected ESCCs and adjacent epithelium. We also analyzed associations between aberrant expression of EZH2 and BMI1, and both clinicopathological findings and outcome. MYC, RB, and P53 expression was examined in selected cases and analyzed in relation to EZH2 expression. Mutations in the P53 gene were evaluated by direct sequencing. EZH2 mRNA expression was investigated in ESCC cell lines with and without P53 transcriptional activity. The results showed that EZH2 protein and BMI1 protein were upregulated in ESCC tissue in comparison with adjacent non-neoplastic epithelium. Aberrant EZH2 and BMI1 protein expression was observed in 19 (14.0%) and 23 (16.9%), respectively, of the 136 ESCCs. Aberrant EZH2 expression was significantly associated with larger size, greater depth of invasion, presence of distant metastasis, and shorter disease-free survival time. Aberrant BMI1 expression was inversely associated with lymph node metastasis and venous invasion, but not associated with survival of the patients. In addition, aberrant EZH2 expression was associated with P53 alteration in ESCC tissue. EZH2 mRNA expression in ESCC cell lines was reduced by activation of P53. In conclusion, P53 alteration may be involved in dysregulated EZH2 expression, and aberrant expression of EZH2 may play a role in ESCC progression.
EZH2 和 BMI1 是转录抑制因子，与人类癌症的进展有关。食管鳞状细胞癌（ESCC）是胃肠道中最具侵袭性的癌之一，通常预后不良。本研究采用免疫组织化学方法检测了 136 例手术切除的 ESCC 及其相邻上皮组织中 EZH2 和 BMI1 的表达，并分析了 EZH2 和 BMI1 异常表达与临床病理特征及预后的关系。在部分病例中检测了 MYC、RB 和 P53 的表达情况，并分析了与 EZH2 表达的关系。通过直接测序评估了 P53 基因突变情况。研究了具有和不具有 P53 转录活性的 ESCC 细胞系中 EZH2 mRNA 的表达情况。结果显示，与相邻非肿瘤上皮组织相比，EZH2 蛋白和 BMI1 蛋白在 ESCC 组织中呈上调表达。在 136 例 ESCC 中，分别有 19 例（14.0%）和 23 例（16.9%）出现 EZH2 和 BMI1 蛋白异常表达。EZH2 异常表达与肿瘤体积较大、浸润深度较深、远处转移和无病生存期较短显著相关。BMI1 异常表达与淋巴结转移和静脉侵犯呈负相关，但与患者的生存无关。此外，EZH2 异常表达与 ESCC 组织中 P53 的改变有关。EZH2 在 ESCC 细胞系中的表达可通过 P53 的激活而降低。综上所述，P53 的改变可能参与了 EZH2 表达的失调，EZH2 的异常表达可能在 ESCC 的进展中发挥作用。
