Zen K, Yasui K, Gen Y, Dohi O, Wakabayashi N, Mitsufuji S, Itoh Y, Zen Y, Nakanuma Y, Taniwaki M, Okanoue T, Yoshikawa T
Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Oncogene. 2009 Aug 13;28(32):2910-8. doi: 10.1038/onc.2009.148. Epub 2009 Jun 8.
The partition-defective 3 (PAR-3) protein is implicated in the formation of tight junctions at epithelial cell-cell contacts. We investigated DNA copy number aberrations in human esophageal squamous cell carcinoma (ESCC) cell lines using a high-density oligonucleotide microarray and found a homozygous deletion of PARD3 (the gene encoding PAR-3). Exogenous expression of PARD3 in ESCC cells lacking this gene enhanced the recruitment of zonula occludens 1 (ZO-1), a marker of tight junctions, to sites of cell-cell contact. Conversely, knockdown of PARD3 in ESCC cells expressing this gene caused a disruption of ZO-1 localization at cell-cell borders. A copy number loss of PARD3 was observed in 15% of primary ESCC cells. Expression of PARD3 was significantly reduced in primary ESCC tumors compared with their nontumorous counterparts, and this reduced expression was associated with positive lymph node metastasis and poor differentiation. Our results suggest that deletion and reduced expression of PARD3 may be a novel mechanism that drives the progression of ESCC.
分隔缺陷蛋白3（PAR-3）参与上皮细胞间紧密连接的形成。我们使用高密度寡核苷酸微阵列研究了人食管鳞状细胞癌（ESCC）细胞系中的DNA拷贝数畸变，发现PARD3（编码PAR-3的基因）存在纯合缺失。在缺乏该基因的ESCC细胞中外源性表达PARD3可增强紧密连接标志物闭合蛋白1（ZO-1）向细胞间接触部位的募集。相反，在表达该基因的ESCC细胞中敲低PARD3会导致ZO-1在细胞间边界的定位破坏。在15%的原发性ESCC细胞中观察到PARD3的拷贝数缺失。与非肿瘤对应组织相比，原发性ESCC肿瘤中PARD3的表达显著降低，且这种表达降低与阳性淋巴结转移和低分化相关。我们的结果表明，PARD3的缺失和表达降低可能是驱动ESCC进展的一种新机制。
