Distinct Pattern of Oncogenic β-catenin Activation in Colorectal Cancer

结直肠癌中致癌 β-连环蛋白激活的独特模式

• 批准号: 13671289
• 负责人: MINAMOTO Toshinari
• 金额: $ 2.3万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671289/
• 关键词: Colorectal cancer; Oncogene; β-catenin; Oncogenic signaling; Molecular diagnosis; APC; K-ras; βTrCP; がん遣伝子; シグナル伝達

It is fairly far from our expectation at the time when β-catenin was first identified as one of the key molecules in cell adhesion machinery that it is in central in the Wnt/ β-catenin/Tcf signaling pathway, which plays pivotal roles in normal embryonic development and differentiation and in malignant transformation of cells. Different mechanisms underlie oncogenic β-catenin acivation ; i.e., mutations in its phospho-acceptor sites, failure to recruit GSK3β because of APC mutation, or inhibition of GSK3β activity by Wnt-secreted proteins or PI3K/Akt signaling ; a consequence of them is abrogation of β-catenin phosphorylation. This leads stabilization of β-catenin and its translocation to the nucleus where it exerts oncogenic activities by transactivating certain effector genes including c-myc, cyclin D1, and MMP-7.Unlike extensive characterization of K-ras that is another oncogene of great interest, many studies to clarify basic mechanisms of β-catenin's oncogenic functions have been c … More ompetitively pursued only in experimental but not clinical settings. It is only in recent years that a small number of reports on oncogenic β-catenin activation and its relevance to patients' pathology have been available for clinical colorectal cancers, showing that oncogenic β-catenin activation is an early event in colorectal cancer development. However, little is known for clinical relevance of this oncogene activation until we currently determined, in this research project, the two distinct patterns of its oncogenic nuclear accumulation (NA), represented by diffuse NA (Nad) and selective NA in the tumor invasion front only (Nainv), respectively as early and presumably late events. The presence of different activation patterns would be supported by evidence that β-catenin is activated in most colon cancers by escaping from a degradation machinery as a result of mutations in APC, which is known to be the earliest genetic alteration in colorectal tumorigenesis, and by our results that, in contrast to Nad pattern, Nainv pattern of β-catenin activation is independent to inactivation of APC. Recently we have obtained a result suggesting that β-transducing repeat-containing protein (βTrCP), a ubiquitin ligase receptor that targets β-catenin for proteasomal degradation, affects different patterns of β-catenin activation in the tumors. Our observation that is more important than the molecular mechanisms underlying the difference in activation patterns was that oncogenic β-catenin activation in the tumor invasion front is an independent and reliable indicator of membership in a subset of colon cancer patients who are highly susceptible to tumor recurrence and have a less favorable survival rate. Furthermore we have demonstrated that although activation of β-catenin and ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes.Apparently, activation of β-catenin is a cosequence, with few exceptions, of its escaping from ubiquitin-mediated protein degradation, the process of which includes a growing numbers of regulators and effectors. More detailed information of the involvement of β-catenin in human cancers is promising for development of molecular diagnosis and treatment targeting this oncogene and regulators/effectors of its signaling. Less

当β-连环蛋白首次被确定为细胞黏附机制的关键分子之一时，它在Wnt/β-连环蛋白/Tcf信号通路中处于中心位置，在正常胚胎发育和分化以及细胞恶性转化中发挥关键作用，这与我们的预期相去甚远。致癌的β-连环蛋白活化有不同的机制，即其磷酸受体位点的突变，由于APC突变而未能募集β，或者通过WNT分泌的蛋白或PI3K/AKT信号抑制GSK3β活性，其结果是β-连环蛋白的磷酸化被取消。这导致β-连环蛋白的稳定及其转位到细胞核，在那里它通过反式激活某些效应基因发挥致癌活性，包括c-myc、细胞周期蛋白d1和基质金属蛋白酶-7。与另一个令人感兴趣的癌基因K-ras的广泛特征不同，许多关于阐明β-连环蛋白致癌功能的基本机制的研究都是c-…更多的是仅在实验中而不是在临床环境中进行研究。直到最近几年，才有少量关于致癌性β-连环蛋白激活及其与患者病理相关性的报道用于临床结直肠癌，表明致癌β-连环蛋白激活是结直肠癌发生发展的早期事件。然而，对于这种癌基因激活的临床相关性知之甚少，直到我们目前在这项研究项目中确定了其致癌核积聚(NA)的两种不同模式，分别代表肿瘤侵袭前沿的弥漫性NA(NAD)和选择性NA(NAIV)，作为早期事件和可能的晚期事件。有证据表明，在大多数结肠癌中，β-连环蛋白是通过逃避降解机制而激活的，这是已知的结直肠肿瘤发生中最早的基因改变。我们的结果支持不同激活模式的存在，与NAD模式相反，β-连环蛋白的Nainv激活模式独立于APC的失活。最近我们获得的结果表明，β转导重复序列蛋白(βTrCP)是一种泛素连接酶受体，针对β-连环蛋白的蛋白酶体降解，影响肿瘤中β-连环蛋白的不同激活模式。我们观察到，比激活模式差异背后的分子机制更重要的是，肿瘤侵袭前沿的致癌β-连环蛋白激活是结肠癌患者子集成员的独立和可靠的指标，这些患者对肿瘤复发高度敏感，生存率较低。此外，我们还发现，虽然β-catenin和ras的激活在临床肿瘤的发展过程中是独立的，但联合分析这两个主要癌基因可以发现大多数结直肠癌并识别出一组预后较差的患者。显然，β-catenin的激活是其逃脱泛素介导的蛋白质降解的一个协同序列，几乎没有例外，这个过程包括越来越多的调节因子和效应器。更详细地了解β-catenin在人类癌症中的作用，有望成为针对该癌基因及其信号调节/效应因子的分子诊断和治疗的发展方向。较少

项目成果

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Minamoto T, Ougolkov A Mai M.: "Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling"Exp Rev Mol Diag.. 2 (6). 565-575 (2002)

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Ougolkov AV、Minamoto T等人：“晚期胃癌中E-钙粘蛋白、β-连环蛋白和c-erbB-2的异常表达：其与肝转移的关系”第四届国际胃癌大会论文集， Monduzzi Editore S. p.，Medimond