The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis.
The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis.
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DOI：
10.1186/1476-4598-8-124
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发表时间：
2009-12-16
期刊：
影响因子：
37.3
通讯作者：
Marra G
中科院分区：
文献类型：
--
作者：
Menigatti M;Cattaneo E;Sabates-Bellver J;Ilinsky VV;Went P;Buffoli F;Marquez VE;Jiricny J;Marra G
人类结肠中的肿瘤发展通常伴随着表观遗传变化，例如DNA甲基化和染色质修饰。这些改变导致基因表达的显著的、可遗传的变化，这有助于选择具有增强的存活潜力的肿瘤细胞。我们小组最近进行的一项高通量基因表达分析确定了许多在结直肠肿瘤中转录明显减少的基因。其中之一，蛋白酪氨酸磷酸酶受体型R（PTPRR）基因，从细胞转化的最早阶段显着下调。在这里，我们表明，两个主要的PTPRR转录变体的水平显着降低（与正常粘膜水平相比），在癌前和癌性结直肠肿瘤，以及在结直肠癌细胞系。PTPRR-1亚型的表达在结直肠癌细胞中由于CpG岛的从头甲基化和转录抑制性组蛋白尾标记（主要是H3 K27 me 3）的富集而失活。PTPRR-1转录起始位点的从头甲基化在29/36（80%）结直肠腺瘤、42/44（95%）结直肠腺癌和8/8（100%）与后一种肿瘤相关的肝转移中得到证实。PTPRR的表观遗传下调似乎是结直肠细胞转化的早期改变，其在与肿瘤进展相关的克隆选择期间维持。它可能代表了RAS/RAF/MAPK/ERK信号传导的组成性激活的初步步骤，这种效应随后将通过编码该途径关键组分的基因突变而得到巩固。
Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential. A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the protein-tyrosine phosphatase receptor type R (PTPRR) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major PTPRR transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the PTPRR-1 isoform was inactivated in colorectal cancer cells as a result of de novo CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3. De novo methylation of the PTPRR-1 transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors. Epigenetic downregulation of PTPRR seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway.
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影响因子：
64.8
作者：
Jepsen, Kristen;Solum, Derek;Rosenfeld, Michael G.
通讯作者：
Rosenfeld, Michael G.
影响因子：
30.8
作者：
Jones, PL;Veenstra, GJC;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
10.5
作者：
Kuzmichev, A;Nishioka, K;Reinberg, D
通讯作者：
Reinberg, D
影响因子：
4.1
作者：
Eswaran, J;Von Kries, JP;Barr, AJ
通讯作者：
Barr, AJ
DOI：
10.1152/ajpgi.1999.277.3.g631
发表时间：
1999-09-01
影响因子：
4.5
作者：
Aliaga, JC;Deschênes, C;Rivard, N
通讯作者：
Rivard, N