SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions
SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions
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DOI：
10.1038/sj.onc.1206807
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发表时间：
2003-08-07
期刊：
影响因子：
8
通讯作者：
Goggins, M
中科院分区：
文献类型：
--
作者：
Sato, N;Fukushima, N;Goggins, M
骨连接蛋白是一种具有多种生物学功能的分泌型糖蛋白，其表达失调与多种癌症的进展有关。使用微阵列，我们以前确定了胰腺癌细胞中DNA甲基化抑制剂治疗诱导的基因之一。因此，我们分析了胰腺癌组织中p53基因的表达模式和甲基化状态。通过寡核苷酸芯片和逆转录-PCR分析的基因表达获利表明，在非肿瘤性胰腺导管上皮细胞中表达，但在大多数胰腺癌细胞系中不表达。TGFAP表达的缺失与其CpG岛的异常高甲基化有关。免疫组化标记显示，在原发性胰腺癌中，在紧邻肿瘤上皮的基质成纤维细胞中，CD 45蛋白过表达，但在癌症本身中很少表达。胰腺癌原代成纤维细胞强烈表达SPARC mRNA并将SPARC蛋白分泌到条件培养基中，用外源性SPARC处理胰腺癌细胞会导致生长抑制。与胰腺癌细胞共培养可增强非癌胰腺组织成纤维细胞中的cDNA 3表达。这些发现表明，在胰腺癌中，β-淀粉样蛋白是异常甲基化的常见靶点，并且在胰腺癌细胞附近的成纤维细胞中β-淀粉样蛋白的表达通过肿瘤-基质相互作用进行调节。
Deregulated expression of SPARC/osteonectin, a secreted glycoprotein with multiple biological functions, has been associated with the progression of various cancers. Using microarrays, we previously identified SPARC as one of the genes induced by treatment with a DNA methylation inhibitor in pancreatic cancer cells. We therefore analysed the expression pattern and methylation status of the SPARC gene in pancreatic cancer. Gene expression profiting by oligonucleotide microarray and reverse transcription-PCR analyses demonstrated that SPARC mRNA was expressed in non-neoplastic pancreatic ductal epithelial cells, but was not expressed in a majority of pancreatic cancer cell lines. The loss of SPARC expression was associated with aberrant hypermethylation of its CpG island. Immunohistochemical labeling revealed that the SPARC protein was overexpressed in the stromal fibroblasts immediately adjacent to the neoplastic epithelium in primary pancreatic cancers, but rarely expressed in the cancers themselves. Primary fibroblasts derived from pancreatic cancer strongly expressed SPARC mRNA and secreted SPARC protein into the conditioned media, and treatment of pancreatic cancer cells with exogenous SPARC resulted in growth suppression. SPARC expression in fibroblasts from noncancerous pancreatic tissue was augmented by coculture with pancreatic cancer cells. These findings suggest that SPARC is a frequent target for aberrant methylation in pancreatic cancer and that SPARC expression in fibroblasts adjacent to pancreatic cancer cells is regulated through tumor-stromal interactions.