Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma.
Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma.
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肝细胞癌中T细胞因子-4同工型 - 反应性靶基因的上调。
DOI：
10.1111/liv.12188
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Kim M
中科院分区：
文献类型：
--
作者：
Tomimaru Y;Koga H;Yano H;de la Monte S;Wands JR;Kim M
Wnt/β-catenin信号通路通过T细胞因子（TCF）-4转录因子蛋白调节参与细胞增殖、存活、迁移和侵袭的基因。然而，在肝细胞癌（HCC）中由选择性剪接事件产生的TCF-4亚型的作用尚不清楚。在这里，我们研究了TCF-4亚型（TCF-4J和K）反应性靶基因，这些基因在肝脏肿瘤发生和肿瘤发展中非常重要。在过表达TCF-4J和K亚型的HCC细胞上进行基因表达芯片。对所选靶基因的表达水平进行评估，并将其表达水平与47对人HCC肿瘤中TCF-4亚型的表达水平进行相关性分析。通过基因表达微阵列的比较显示，与表达TCF-4K的细胞相比，TCF-4J中447个基因上调，343个基因下调超过2.0倍。我们在47对人HCC和邻近的未受累肝组织中验证了18个选定的参与Wnt/β-catenin、胰岛素/IGF-1/IRS 1和Notch信号通路的靶基因的表达。观察到HCC细胞中TCF-4J亚型激活的13个基因（CLDN 2、STK 17 B、SPP 1、AXIN 2、WISP 2、MMP 7、IRS 1、ANXA 1、CAMK 2N 1、ASPH、GPR 56、CD 24和JAG 1）在HCC肿瘤中也比邻近瘤周组织上调;更重要的是，10个基因与肿瘤中TCF-4J表达水平显著相关。TCF-4亚型（TCF-4J和K）在HCC中激活不同的下游靶基因。TCF-4J亚型表达的生物学后果是与三联Wnt/β-catenin、胰岛素/IGF-1/IRS 1和Notch信号转导通路激活相关的基因上调，这有助于HCC的发病。
The Wnt/β-catenin signaling pathway regulates genes involved in cell proliferation, survival, migration, and invasion through regulation by T-cell factor (TCF)-4 transcription factor proteins. However, the role of TCF-4 isoforms generated by alternative splicing events in hepatocellular carcinoma (HCC) is unknown. Here we investigated TCF-4 isoforms (TCF-4J and K)-responsive target genes that are important in hepatic oncogenesis and tumor development. Gene expression microarray was performed on HCC cells overexpressing TCF-4J and K isoforms. Expression level of selected target genes was evaluated and correlations were made between their expression level and that of TCF-4 isoform in 47 pairs of human HCC tumors. Comparison by gene expression microarray revealed that 447 genes were upregulated and 343 downregulated more than 2.0-fold in TCF-4J compared to TCF-4K expressing cells. We validated expression of 18 selected target genes involved in Wnt/β-catenin, insulin/IGF-1/IRS1, and Notch signaling pathways in 47 pairs of human HCCs and adjacent uninvolved liver tissues. It was observed that 13 genes (CLDN2, STK17B, SPP1, AXIN2, WISP2, MMP7, IRS1, ANXA1, CAMK2N1, ASPH, GPR56, CD24, and JAG1) activated by TCF-4J isoform in HCC cells, were also upregulated in HCC tumors compared to adjacent peritumor tissue; more important, 10 genes exhibited a significant correlation with the TCF-4J expression level in tumor. TCF-4 isoforms (TCF-4J and K) activated different downstream target genes in HCC. The biologic consequence of TCF-4J isoform expression was upregulation of genes associated with tripartite Wnt/β-catenin, insulin/IGF-1/IRS1, and Notch signal transduction pathway activation, which contributes to the pathogenesis of HCC.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
15.9
作者：
Lavaissiere, L;Jia, S;Friedman, PA
通讯作者：
Friedman, PA
影响因子：
25.7
作者：
de la Monte, SM;Tamaki, S;Wands, JR
通讯作者：
Wands, JR
影响因子：
13.5
作者：
Boyault, Sandrine;Rickman, David S.;Zucman-Rossi, Jessica
通讯作者：
Zucman-Rossi, Jessica
影响因子：
13.5
作者：
Cantarini, M. Chiara;de la Monte, Suzanne M.;Wands, Jack R.
通讯作者：
Wands, Jack R.