Distinct Pattern of Oncogenic β-catenin Activation in Colorectal Cancer

β-catenin作为细胞粘附机制的关键分子之一，在Wnt/ β-catenin/Tcf信号通路中处于中心位置，在正常胚胎发育分化和细胞恶性转化中起关键作用，这与我们最初的预期相去甚远。致癌β-连环蛋白激活的不同机制例如，其磷酸化受体位点发生突变，APC突变导致GSK3β募集失败，或wnt分泌蛋白或PI3K/Akt信号通路抑制GSK3β活性；它们的一个后果是β-连环蛋白磷酸化的废除。这导致β-catenin稳定并易位到细胞核，通过激活某些效应基因（包括c-myc、cyclin D1和MMP-7）发挥致癌活性。与K-ras（另一种非常有趣的致癌基因）的广泛表征不同，许多阐明β-catenin致癌功能的基本机制的研究都是在实验环境中进行的，而不是在临床环境中。直到最近几年，临床结直肠癌中才有少量关于β-catenin的致癌激活及其与患者病理相关性的报道，表明β-catenin的致癌激活是结直肠癌发展的早期事件。然而，对于这种癌基因激活的临床相关性知之甚少，直到我们目前在本研究项目中确定了其致癌核积累（NA）的两种不同模式，即仅在肿瘤侵袭前沿的弥漫性NA （Nad）和选择性NA (Nainv)，分别为早期和可能的晚期事件。不同激活模式的存在将得到以下证据的支持：β-catenin在大多数结肠癌中因APC突变而脱离降解机制而被激活，这是已知的结直肠肿瘤发生中最早的遗传改变，并且我们的结果表明，与Nad模式相反，β-catenin激活的Nainv模式与APC失活无关。最近我们获得的结果表明，β-转导重复包含蛋白（βTrCP）是一种泛素连接酶受体，靶向β-连环蛋白进行蛋白酶体降解，影响肿瘤中β-连环蛋白的不同激活模式。我们的观察结果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-catenin激活是结肠癌患者亚群成员的独立可靠指标，这些患者对肿瘤复发非常敏感，生存率较低。此外，我们已经证明，尽管β-catenin和ras的激活在临床癌症发展过程中是独立的，但结合分析这两种主要癌基因可以检测大多数结直肠癌，并识别出预后较差的患者亚群。显然，β-连环蛋白的激活是其从泛素介导的蛋白质降解中逃逸的结果，这一过程包括越来越多的调节因子和效应因子。更多关于β-连环蛋白参与人类癌症的详细信息，为开发针对该癌基因及其信号传导调节因子/效应器的分子诊断和治疗提供了希望。少

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