Activation and regulation of oncogenic signaling networks in colorectal cancer

当前癌症研究的一个有前景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、分化和程序性细胞死亡）。其中一个事件发生在Wnt信号通路上，其异常激活参与细胞的恶性转化，β-catenin具有两种不同的功能，即维持细胞间粘附和介导Wnt/β-catenin通路，在胚胎发生和某些肿瘤，特别是结直肠癌（CRC）的发生和进展中起关键作用^<16>。基于我们之前的研究表明，β-catenin的不同激活模式与肿瘤的恶性潜能和CRC患者的临床结局有关^6，在本研究中，我们探讨了Wnt/β-catenin信号在结直肠癌中的激活和解除。Wnt/β-catenin信号的致癌特性源于β-catenin从细胞膜到细胞核的泛素介导的降解和亚细胞定位的改变，在那里它与T细胞因子（Tcf）结合；该复合物促进编码细胞增殖因子和抑制细胞凋亡的基因转录。我们之前发现，β-转导重复蛋白（β-TrCP）是泛素连接酶复合物的一个组成部分，靶向β-catenin和i -κB α进行蛋白酶体降解，因此是Wnt/β-catenin信号通路的负调节因子和NF-κB通路的正调节因子。通过β-catenin/Tcf途径诱导β-TrCP增加导致β-catenin降解，表明生理条件下β-catenin/Tcf途径受负反馈回路控制（Mol Cell 2000;5:877-82）。本研究表明，在结直肠癌中，β-TrCP和β-catenin之间的负反馈回路调节受损导致β-TrCP表达增加，与β-catenin和NF-κB的激活有关，表明β-TrCP过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^9。如上所述，在携带野生型CTNNB1和APC基因的非肿瘤细胞中，β-catenin/Tcf信号以Tcf依赖的方式增加β-TrCP mRNA和蛋白的水平（Mol Cell 2000;5:877-82）。在这项研究中，我们鉴定了一个新的β-catenin/Tcf靶基因X；结合β-TrCP1 mRNA编码区并使其稳定的蛋白产物。研究还表明，在结肠癌细胞中，X蛋白是通过β-catenin/Tcf信号诱导β-TrCP1 mRNA和c-myc mRNA的必需蛋白。在人类结直肠癌中，X蛋白和β-TrCP的表达增加与同一肿瘤中β-catenin和NF-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）。关于GSK3β是Wnt信号的负调节因子的经典观点，人们可以认为它在CRC中起着类似肿瘤抑制因子的作用。据报道，GSK3β具有相反的作用；通过磷酸化依赖性降解泛素系统中的β-catenin去除肿瘤触发因子，并通过NF-κB途径维持细胞存活和增殖。在这里，我们通过转录和药理学调节GSK3β的表达和活性，证明了GSK3β在CRC中未被认识的作用（肿瘤支持特性），并证明了该激酶作为CRC^<14 bb0的潜在治疗靶点。少

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