Associations among β-TrCP, an E3 ubiquitin ligase receptor, β-catenin, and NF-κB in colorectal cancer
Associations among β-TrCP, an E3 ubiquitin ligase receptor, β-catenin, and NF-κB in colorectal cancer
复制标题
DOI：
10.1093/jnci/djh219
复制
发表时间：
2004-08-04
影响因子：
10.3
通讯作者：
Minamoto, T
中科院分区：
文献类型：
--
作者：
Ougolkov, A;Zhang, B;Minamoto, T
背景：泛素-蛋白酶体通路在调节参与肿瘤发生的蛋白质信号通路中起重要作用。含有β-转导蛋白重复序列的蛋白（β-TrCP）是靶向β-连环蛋白和I κ B α的泛素连接酶复合物的组分，用于蛋白酶体降解，因此是Wnt/β-连环蛋白信号传导的负调节剂和NF-κ B信号传导的正调节剂。我们分析了β-TrCP在结直肠癌中的表达及其与β-连环蛋白亚细胞定位类型的相关性，β-连环蛋白亚细胞定位是一种间接的激活措施。研究方法：采用定量逆转录-聚合酶链反应和免疫印迹法分别检测45例结直肠癌患者肿瘤和正常组织中β-TrCP 1 mRNA和蛋白水平。通过免疫组织化学检测β-连环蛋白激活类型（弥漫或浸润边缘）和NF-κ B激活。采用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸-生物素缺口末端标记法（TUNEL）检测细胞凋亡。所有统计学检验均为双侧检验。结果：与正常组织相比，45例肿瘤中有25例（56%）β-TrCP 1 mRNA和蛋白水平升高。在22例（49%）β-连环蛋白激活的肿瘤中，12例为弥漫型（即，整个肿瘤的核积聚）和10个具有侵袭边缘型（即，主要在形成侵袭边缘的肿瘤细胞中的核积聚）。β-TrCP 1水平的增加与β-连环蛋白激活（P = 0.023）和细胞凋亡减少（P = 0.035）在统计学上显著相关。β-TrCP在肿瘤细胞的细胞核中积累，所述肿瘤细胞含有增加水平的β-TrCP 1 mRNA和活性形式的NF-κ B。在有转移的患者的原发肿瘤中检测到更高水平的β-TrCP 1 mRNA（0.960任意单位，95%置信区间= 0.878至1.042），而在没有转移的患者的肿瘤中检测到更高水平的β-TrCP 1 mRNA（0.722任意单位，95%置信区间= 0.600至0.844; P = 0.016）。结论：在结直肠癌中，β-TrCP 1表达的增加与β-连环蛋白和NF-κ B的激活相关，表明通过增加β-TrCP表达整合这些信号通路可能有助于抑制细胞凋亡和肿瘤转移。
Background: The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation. Methods: Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided. Results: Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P = .023) and decreased apoptosis (P = .035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P = .016). Conclusion: In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.