Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
Int J Oncol. 2015 Nov;47(5):1811-8. doi: 10.3892/ijo.2015.3167. Epub 2015 Sep 16.
Esophageal squamous cell carcinoma (ESCC), the most common esophageal cancer in East Asia, is among the six cancers with the highest fatality rates worldwide. Unfortunately, multidisciplinary treatment strategies have not achieved satisfactory outcomes. Therefore, novel insights into the molecular biology of ESCC are required to improve treatment. The gene encoding the transmembrane adherens junctions-associated protein-1 (AJAP1) expressed by epithelial cells resides in chromosome 1p36, which is frequently lost or epigenetically silenced in several malignancies. Here, we investigated the expression levels and regulatory mechanism of AJAP1 transcription. We determined the levels of AJAP1 mRNA and the genes encoding potentially interacting proteins expressed by ESCC cell lines, as well as the chromosomal copy number of AJAP1 and the methylation status of its promoter region. AJAP1 mRNA levels of 78 pairs of surgically resected specimens were determined to evaluate the association of AJAP1 expression and clinicopathological factors. Nine ESCC cell lines differentially expressed AJAP1 mRNA, and demethylation of hypermethylated AJAP1 genomic DNA reactivated AJAP1 mRNA expression. The copy number of sequences upstream or downstream of the AJAP1 transcriptional start site was not detectably altered. AJAP1 mRNA levels correlated inversely with those of ezrin (EZR) and were significantly lower in ESCC tissues compared with adjacent normal tissues. AJAP1 mRNA levels decreased gradually with increasing tumor stage. Patients with downregulated AJAP1 transcription were more likely to experience shorter overall and disease-free survival. Multivariate analysis of disease-free survival identified downregulated AJAP1 transcription as an independent prognostic factor. These results suggest that in ESCC, AJAP1 acts as a putative tumor suppressor and that AJAP1 transcription is regulated by promoter hypermethylation. These findings indicate that downregulated AJAP1 transcription may serve as a novel tumor biomarker to predict recurrence of ESCC after esophagectomy.
食管鳞状细胞癌（ESCC）是东亚最常见的食管癌，是全球六种死亡率最高的癌症之一。不幸的是，多学科治疗策略并未取得令人满意的结果。因此，需要深入了解 ESCC 的分子生物学，以改善治疗效果。编码上皮细胞表达的跨膜黏着连接相关蛋白 1（AJAP1）的基因位于 1p36 染色体上，在几种恶性肿瘤中经常丢失或表观遗传沉默。在这里，我们研究了 AJAP1 转录的表达水平和调控机制。我们确定了 ESCC 细胞系中 AJAP1 mRNA 及其编码潜在相互作用蛋白的表达水平，以及 AJAP1 的染色体拷贝数和启动子区域的甲基化状态。通过检测 78 对手术切除标本中 AJAP1 的 mRNA 水平，评估 AJAP1 表达与临床病理因素的关系。9 种 ESCC 细胞系中 AJAP1 mRNA 表达存在差异，且去甲基化的 AJAP1 基因组 DNA 可重新激活 AJAP1 mRNA 的表达。AJAP1 转录起始位点上下游序列的拷贝数未发生明显改变。AJAP1 mRNA 水平与 ezrin（EZR）呈负相关，并且在 ESCC 组织中明显低于相邻的正常组织。AJAP1 mRNA 水平随着肿瘤分期的增加而逐渐降低。转录下调 AJAP1 的患者总生存期和无病生存期更短。无病生存期的多变量分析将 AJAP1 转录下调确定为独立的预后因素。这些结果表明，在 ESCC 中，AJAP1 作为一种潜在的肿瘤抑制因子，其转录受启动子甲基化的调控。这些发现表明，下调的 AJAP1 转录可能作为一种新的肿瘤标志物，用于预测 ESCC 手术后的复发。
