Loss of exon 4 in a human T-cell factor-4 isoform promotes hepatic tumourigenicity.
Loss of exon 4 in a human T-cell factor-4 isoform promotes hepatic tumourigenicity.
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DOI：
10.1111/liv.12189
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发表时间：
2013-11
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;Xu CQ;Nambotin SB;Yan T;Wands JR;Kim M
T细胞因子（TCF）蛋白代表激活Wnt/β-连环蛋白信号传导的关键转录因子。我们已经报道了一对TCF-4亚型（TCF-4C和TCF-4D）在肝细胞癌（HCC）细胞中表现出不同的TCF转录活性，尽管它们的结构仅因外显子4的存在（TCF-4D）或缺失（TCF-4C）而不同。证实外显子4在肝癌发生中的调节作用。TCF-4C和TCF-4D在27对人HCC和癌旁肝组织中的表达谱进行了检测。使用过表达TCF-4同种型的稳定克隆，在OUMS-29（永生化肝细胞衍生的）和HAK-1A（分化良好的HCC）细胞系中评价TCF-4同种型的功能作用。TCF-4C在HCC组织中的表达显著高于相应的癌旁组织和正常肝组织;相反，TCF-4D的表达没有差异。与TCF-4D克隆相比，来自两种细胞系的TCF-4C克隆表现出增加的TCF活性、Wnt响应性靶基因、细胞增殖、细胞周期进展和对化疗药物的抗性。TCF-4C克隆的细胞迁移和集落形成能力显著高于TCF-4D克隆。在裸鼠异种移植模型中，与TCF-4D克隆相比，HAK-1A衍生的TCF-4C克隆快速发展肿瘤。TCF-4C克隆衍生的肿瘤与缓慢发展的小TCF-4D衍生的肿瘤相比，表现出Wnt响应性靶基因的上调。这些结果表明，与携带外显子4的TCF-4D同种型相比，缺乏外显子4的TCF-4C同种型与恶性表型相关，表明TCF-4的外显子4在HCC发展中起着重要作用。
T-cell factor (TCF) proteins represent key transcription factors that activate Wnt/β-catenin signaling. We have reported that a pair of TCF-4 isoforms (TCF-4C and TCF-4D) exhibits differential TCF transcriptional activity in hepatocellular carcinoma (HCC) cells, although their structure differs by only the presence (TCF-4D) or absence (TCF-4C) of exon 4. To demonstrate a regulatory role of exon 4 in HCC development. TCF-4C and TCF-4D expression profiles were examined in 27 pairs of human HCC and adjacent liver tissues. The functional role of the TCF-4 isoforms was evaluated in OUMS-29 (an immortalized hepatocyte-derived) and HAK-1A (a well differentiated HCC) cell lines using stable clones overexpressing the TCF-4 isoforms. TCF-4C was significantly upregulated in HCC tissues compared to corresponding peritumor and normal liver tissues; in contrast, there was no difference of TCF-4D expression. TCF-4C clones derived from both cell lines exhibited increased TCF activity, Wnt-responsive target genes, cell proliferation, cell cycle progression, and resistance to chemotherapeutic drugs compared to TCF-4D clones. Capability of cell migration and colony formation was significantly higher in TCF-4C than TCF-4D clones. In a nude mice xenograft model, the HAK-1A-derived TCF-4C clone rapidly developed tumors compared to the TCF-4D clone. TCF-4C clone-derived tumors exhibited upregulation of Wnt-responsive target genes compared to the slow developing and small TCF-4D-derived tumors. These results demonstrate that the TCF-4C isoform lacking exon 4 is associated with a malignant phenotype compared to the exon 4-harboring TCF-4D isoform, indicating that exon 4 of TCF-4 plays a prominent role in HCC development.
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影响因子：
13.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
23.9
作者：
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