Potential biomarkers of colorectal adenoma-dysplasia-carcinoma progression: mRNA expression profiling and in situ protein detection on TMAs reveal 15 sequentially upregulated and 2 downregulated genes.
Potential biomarkers of colorectal adenoma-dysplasia-carcinoma progression: mRNA expression profiling and in situ protein detection on TMAs reveal 15 sequentially upregulated and 2 downregulated genes.
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DOI：
10.3233/clo-2009-0458
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Molnár B
中科院分区：
文献类型：
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作者：
Galamb O;Sipos F;Spisák S;Galamb B;Krenács T;Valcz G;Tulassay Z;Molnár B
背景：由于大多数结直肠癌（CRC）是由绒毛腺瘤发展而来，研究结直肠腺瘤-发育不良-癌序列中基因表达谱的改变可能会产生疾病进展的潜在生物标志物。方法：从15例结直肠癌患者、15例绒毛腺瘤患者和8例正常人的结肠活检中提取、扩增和生物素化总RNA。使用HGU133Plus2.0微阵列评估基因表达谱，并使用RT-PCR验证疾病进展相关数据。使用103名独立患者和16名重叠患者的组织微阵列样本在蛋白质水平上测试了潜在的生物标志物。结果：17个基因在正常-腺瘤-发育不良-癌的过程中依次表达改变。前列腺素- d2受体（PTGDR）和无羊膜同源基因（AMN）表达逐渐降低，其余15个基因包括骨连接蛋白、骨桥蛋白、胶原iv - α 1、biglycan、基质GLAprotein、血管性血液病因子表达逐渐升高。在蛋白水平上，PTGDR、AMN、骨桥蛋白和骨连接蛋白的表达趋势相似。结论：AMN和PTGDR的下调以及骨桥蛋白和骨连接蛋白的上调被发现是结直肠癌发生和疾病进展的潜在生物标志物，可用于mRNA和蛋白水平的前瞻性活检筛查。这里发现的基因改变也可能增加我们对结直肠癌进展的理解。
Background: As most colorectal cancers (CRC) develop from villous adenomas, studying alterations in gene expression profiles across the colorectal adenoma–dysplasia–carcinoma sequence may yield potential biomarkers of disease progression. Methods: Total RNA was extracted, amplified, and biotinylated from colonic biopsies of 15 patients with CRC, 15 with villous adenoma and 8 normal controls. Gene expression profiles were evaluated using HGU133Plus2.0 microarrays and disease progression associated data were validated with RT-PCR. The potential biomarkers were also tested at the protein level using tissue microarray samples of 103 independent and 16 overlapping patients. Results: 17 genes were validated to show sequentially altered expression at mRNA level through the normal–adenoma–dysplasia–carcinoma progression. Prostaglandin-D2 receptor (PTGDR) and amnionless homolog (AMN) genes revealed gradually decreasing expression while the rest of 15 genes including osteonectin, osteopontin, collagen IV–alpha 1, biglycan, matrix GLAprotein, and von Willebrand factor demonstrated progressively increasing expression. Similar trends of expression were confirmed at protein level for PTGDR, AMN, osteopontin and osteonectin. Conclusion: Downregulated AMN and PTGDR and upregulated osteopontin and osteonectin were found as potential biomarkers of colorectal carcinogenesis and disease progression to be utilized for prospective biopsy screening both at mRNA and protein levels. Gene alterations identified here may also add to our understanding of CRC progression.