Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma
Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma
复制标题
DOI：
10.1002/ijc.20118
复制
发表时间：
2004-06-10
影响因子：
6.4
通讯作者：
Tanzawa, H
中科院分区：
文献类型：
--
作者：
Endo, Y;Uzawa, K;Tanzawa, H
编码SERCA2的Atp2a2基因（Atp2a2(+/-)）杂合缺失的小鼠会自发地发生皮肤和上消化道（包括口腔）的SCCs。为了阐明ATP2A2在人类口腔癌发生中的作用，我们分析了原发性OSCCs和opl的遗传和表观遗传变化以及mRNA和蛋白的表达。除了一个oscc来源的细胞系显示12bp的ATP2A2缺失外，我们在原代OSCC-s （n = 52）、opl （n = 32）和细胞系（n = 8）中未发现该基因编码序列突变。然而，在免疫组织化学中，ATP2A2的高频率下调不仅在原发性OSCCs中明显（42%,42/100），而且在opl中也很明显（31%,10/32）。实时定量RT-PCR数据与蛋白表达状态一致。在30例ATP2A2下调的OSCCs中，有9例检测到ATP2A2 DNA甲基化异常。此外，在DNA去甲基化剂5-aza-2’-dC处理后，大多数显示ATP2A2甲基化的细胞系都能诱导ATP2A2蛋白的恢复或表达升高。这些结果表明，ATP2A2基因失活在口腔癌发生过程中是一个频繁和早期的事件，表达丧失可能部分受到表观遗传机制的调节。(C) 2004 Wiley-Liss, Inc。
Mice with a heterozygous deletion of the Atp2a2 gene (Atp2a2(+/-)) encoding SERCA2 spontaneously develop SCCs of the skin and upper digestive tract, including the oral cavity. To elucidate the contribution of ATP2A2 to human oral carcinogenesis, we analyzed genetic and epigenetic changes as well as mRNA and protein expression in primary OSCCs and OPLs. With the exception of one OSCC-derived cell line showing a 12 bp deletion of ATP2A2, we found no mutations in the coding sequence of the gene in primary OSCC-s (n = 52), OPLs (n = 32) and cell lines (n = 8). In immunohistochemistry, however, high frequencies of ATP2A2 downregulation were evident not only in primary OSCCs (42%, 42/100) but also in OPLs (31%, 10/32). Real-time quantitative RT-PCR data were consistent with the protein expression status. Aberrant DNA methylation within ATP2A2 also was detected in 9 of 30 ATP2A2-downregulated OSCCs. Moreover, restoration or elevated expression of the ATP2A2 protein was induced in most of the cell lines showing ATP2A2 methylation after treatment with 5-aza-2'-dC, a DNA demethylating agent. These results suggest that inactivation of the ATP2A2 gene is a frequent and early event during oral carcinogenesis and that loss of expression may be regulated partly by an epigenetic mechanism. (C) 2004 Wiley-Liss, Inc.