权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Activation and regulation of oncogenic signaling networks in colorectal cancer

结直肠癌致癌信号网络的激活和调节

基本信息

批准号：
15390391
负责人：
MINAMOTO Toshinari
金额：
$ 6.08万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390391/
关键词：
Colorectal cancer Oncogenic signaling β-catenin Ubiquitin system β-TrCP NF-κB RNA trans-acting factor GSK3β がん分子標的 ELISA 血清分子診断大腸がんユビキチン化分解 β-TrCP E3ユビキチンリガーゼ分子標的 RASがん化シグナル

项目摘要

A promising area in current cancer research explores the wide range of molecular events including aberrant/alternative gene splicing, epigenetic changes, cellular signal transduction, transcriptional regulation and post-translational modifications, which determine the fate of cells (growth, differentiation, and programmed cell death). One of such events takes place in the Wnt signaling pathway, and its aberrant activation is involved in malignant transformation of cells, β-catenin has two distinct functions, namely, maintaining cell-to-cell adhesion and mediating the Wnt/β-catenin pathway, which plays pivotal roles in embryogenesis and in certain tumors, particularly development and progression of colorectal cancer (CRC)^<16>. On the basis of our previous studies showing association of distinct patterns of β-catenin activation with malignant potential of the tumors and clinical outcome of CRC patients^6, in the present study we addressed the molecular and cellular mechanisms underlying … More activation and deregulation of Wnt/β-catenin signaling in colorectal cancer.The oncogenic properties of Wnt/β-catenin signaling stem from alteration in ubiquitin-mediated degradation and subcellular localization of β-catenin from cell membrane to the nucleus, where it binds to T cell factor (Tcf) ; the complex facilitates transcription of genes encoding factors for cell proliferation and inhibition of apoptosis. We previously found that β-transducin repeat-containing protein (β-TrCP) is a component of the ubiquitin ligase complex targeting β-catenin and IκBα for proteasomal degradation and thus a negative regulator of Wnt/β-catenin signaling and a positive regulator of NF-κB pathway. Increased induction of β-TrCP via the β-catenin/Tcf pathway results in degradation of β-catenin, indicating that a negative feedback loop controls the β-catenin/Tcf pathway under physiologic conditions (Mol Cell 2000;5:877-82). Here we demonstrated that, in CRC, increased expression of β-TrCP by an impairment in the negative feedback loop regulation between β-TrCP and β-catenin is associated with activation of both β-catenin and NF-κB, suggesting that the integration of these signaling pathways by β-TrCP overexpresion contributes to an inhibition of apoptosis and tumor metastasis^9.As mentioned above, in non-neoplastic cells harboring wild-type CTNNB1 and APC genes, β-catenin/Tcf signaling increases levels of β-TrCP mRNA and protein in a Tcf-dependent manner (Mol Cell 2000;5:877-82). In this study, we identified a novel β-catenin/Tcf target gene X ; protein product of which binds to the coding region of β-TrCP1 mRNA and stabilizes it. It was also demonstrated that X protein is essential for induction of mRNA of β-TrCP1 as well as c-myc by β-catenin/Tcf signaling in colon cancer cells. In human CRC, increased expression of X protein and β-TrCP coincides with activation of β-catenin and NF-κB in the same tumor, which is associated, with inhibition of apoptosis and tumor metastasis (unpublished data).With regards to the canonical view that GSK3β is a negative regulator of Wnt signaling, one may consider that it functions like a tumor suppressor in CRC. Reportedly GSK3β has opposing roles ; removing a neoplastic trigger by phosphorylation-dependent degradation of β-catenin in the ubiquitin system, and maintaining cell survival and proliferation through the NF-κB pathway. Here we demonstrated an unrecognized role (tumor supportive properties) of GSK3β in CRC by transcriptionally and pharmacologically modulating its expression and activity, and warrant proposing this kinase as a potential therapeutic target in CRC^<14>. Less

当前癌症研究的一个有希望的领域是探索广泛的分子事件，包括异常/替代基因剪接、表观遗传学变化、细胞信号转导、转录调控和翻译后修饰，这些事件决定了细胞的命运(生长、分化和细胞程序性死亡)。其中之一发生在Wnt信号通路中，其异常激活参与了细胞的恶性转化，β-catenin具有两个不同的功能，即维持细胞与细胞间的黏附和介导Wnt/β-catenin通路，在胚胎发育和某些肿瘤，特别是结直肠癌的发生和发展中起着关键作用。基于我们先前的研究表明β-连环蛋白激活的不同模式与肿瘤的恶性潜能和结直肠癌患者的临床转归有关，在本研究中，我们探讨了…的分子和细胞机制。Wnt/β-catenin信号在结直肠癌中的更多激活和失控。Wnt/β-catenin信号的致癌特性源于泛素介导的降解和β-catenin从细胞膜到细胞核的亚细胞定位的改变，在那里它与T细胞因子(Tcf)结合；该复合体促进编码细胞增殖和抑制凋亡的因子的转录。我们先前发现，β-转导蛋白重复序列蛋白(β-TrCP)是泛素连接酶复合体的一种成分，针对β-连环蛋白和I-κBα的蛋白酶体降解，因此是WNT/β-连环蛋白信号的负调节因子和核因子-κB途径的正调节因子。通过β-连环蛋白/Tcf途径诱导的β-TrCP增加导致β-连环蛋白的降解，表明在生理条件下，负反馈环控制β-连环蛋白/Tcf途径(Mol Cell2000；5：877-82)。在这里，我们证明，在结直肠癌中，β-TrCP的表达增加是由于β-TrCP和β-Catenin之间的负反馈环路调节受损，与β-Catenin和NF-κB的激活有关，这表明β-TrCP的过度表达整合了这些信号通路，有助于抑制细胞凋亡和肿瘤转移。在本研究中，我们发现了一个新的β-连环蛋白/Tcf靶基因X，其蛋白产物与β-TrCP1mRNA的编码区结合并使其稳定。研究还表明，X蛋白在β-连环蛋白/Tcf信号通路中对β-TrCP1mRNA和c-mycmRNA的诱导是必不可少的。在人类结直肠癌中，X蛋白和β-TrCP的表达增加与β-连环蛋白和核因子-κB的激活相一致，这与抑制细胞凋亡和肿瘤转移有关(未发表的数据)。考虑到经典的观点，即β是Wnt信号的负调控因子，人们可以认为它在结直肠癌中的作用类似于肿瘤抑制因子。据报道，GSK3β具有相反的作用：通过泛素系统中依赖磷酸化的β-连环蛋白的降解来消除肿瘤触发，并通过核因子-κB途径维持细胞的生存和增殖。在这里，我们通过转录和药物调节Gsk3β的表达和活性，证明了Gsk3在结直肠癌中的一个未知的作用(肿瘤支持特性)，并保证将其作为结直肠癌的潜在治疗靶点。较少