Saeki H, Tanaka S, Tokunaga E, Kawaguchi H, Ikeda Y, Maehara Y, Sugimachi K
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Oncology. 2001;61(2):156-61. doi: 10.1159/000055367.
Disruption of the APC/beta-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.
APC/β-连环蛋白/Tcf信号通路的破坏被认为是癌症发生发展中的一个重要步骤。据报道，Tcf-4转录因子基因是微卫星不稳定（MSI）的结直肠癌中MSI的靶点之一。我们对41例日本MSI胃肠道肿瘤患者以及癌细胞系中的Tcf-4基因进行了测序分析。21例（14.3%）MSI结直肠癌中有3例含有突变的Tcf-4基因，该基因在（A）9重复序列中编码1个碱基缺失，导致Tcf-4蛋白的羧基末端截短。在20例MSI胃癌或胃癌细胞系中未检测到Tcf-4突变。此外，我们发现了Tcf-4基因的一种新转录本，其在Tcf-4编码序列的（A）9重复序列之前含有一段73 bp的片段。测序分析显示，插入片段与Tcf-1基因的IXA外显子的片段有60%的同源性。有趣的是，这种插入导致Tcf-4截短，类似于（A）9重复序列中的1个碱基缺失。因此，在部分日本MSI结直肠癌中，Tcf-4的移码突变可能具有功能意义。胃肠道肿瘤发生过程中Tcf-4信号网络的功能改变需要进一步研究。
