School of Life Sciences and Biotechnology, Korea University, 136-701, Seoul, Republic of Korea.
Cell Oncol (Dordr). 2013 Apr;36(2):141-53. doi: 10.1007/s13402-012-0119-z. Epub 2012 Dec 21.
CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus. In addition, CD81 has been suggested to be involved in a broad range of other cellular functions. Its putative implication in tumorigenesis has so far, however, remained largely unexplored. To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development, we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines.
The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated.
CD81 mRNA levels were found to be low in 16 of 40 (40 %) primary tumors and 9 of 14 (64.2 %) cell lines, and these low expression levels were found to correlate with the stage and grade of the tumors. Genomic alterations of CD81 were not encountered, whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment. Bisulfite DNA sequencing analysis of 10 CpG sites within the 5' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation. Subsequent restoration of CD81 expression induced a G1 cell cycle arrest and apoptosis, whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli. Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation, respectively. CD81 was found to inhibit p38 (but not ERK, JNK and AKT) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation.
From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells, at least partially through p38 signaling.
CD81 是一种跨膜蛋白，作为丙型肝炎病毒的假定受体。此外，CD81 还被认为参与了广泛的其他细胞功能。然而，其在肿瘤发生中的假定作用迄今在很大程度上仍未得到探索。为了评估 CD81 在胃癌发生中作为肿瘤抑制因子的候选性，我们在一系列原发性胃癌肿瘤和胃癌衍生细胞系中研究了其表达和功能。
评估了 CD81 基因的表达及其伴随的甲基化状态及其对肿瘤发生和细胞信号转导的影响。
在 40 个原发性肿瘤中的 16 个（40%）和 14 个细胞系中的 9 个（64.2%）中发现 CD81 mRNA 水平较低，并且这些低表达水平与肿瘤的分期和分级相关。未发现 CD81 的基因组改变，而在低表达细胞中用 5-aza-dC 处理可重新激活其表达。对 CD81 基因启动子 5'近端区域内的 10 个 CpG 位点的亚硫酸氢盐 DNA 测序分析表明，观察到的转录沉默与异常的高甲基化紧密相关。随后恢复 CD81 表达诱导 G1 细胞周期停滞和凋亡，而 siRNA 介导的 CD81 下调促进细胞增殖并减弱细胞对各种凋亡应激刺激的反应。此外，通过 CD81 的上调和下调，肿瘤细胞的集落形成能力也可以被抑制和增强。发现 CD81 抑制 p38（但不抑制 ERK、JNK 和 AKT）磷酸化，并且通过 p38 的上调和下调可以消除其生长抑制作用。
从我们的数据中我们得出结论，CD81 的表观遗传失活是胃癌的一个共同特征，这种失活可能使肿瘤细胞获得生长和存活优势，至少部分通过 p38 信号转导。
