PO.CL01.16 · 临床研究
MLK4表达与结肠癌患者生存之间的关联
Association between MLK4 expression and colon cancer patient survival
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：混合谱系激酶4（MLK4）是丝氨酸/苏氨酸激酶家族的一种蛋白激酶，通过MAPK通路发挥功能。MLK4与结肠癌肿瘤学结局的关联尚未得到充分描述。我们旨在利用TCGA数据库研究MLK4在蛋白和mRNA水平的分子表达、其在不同分期间的差异表达，以及在表达升高的病例中与生存的关联。
方法：使用TCGA数据库对结直肠癌中的MLK4进行了计算机模拟分析，对288名患者进行了分期表达和总生存分析。使用一个结肠癌及配对相邻正常结肠组织的TMA（组织微阵列），并标注了生存数据和临床分期（AJCC第8版），以研究MLK4在结肠癌中的差异表达。对由正常组织和肿瘤组成的FFPE样本进行了激光捕获显微切割。使用有机提取和RT-PCR技术定量MLK4 RNA。
结果：对74对配对样本的MLK4 IHC显示，与正常组织相比，结肠癌中MLK4表达显著升高（p < 0.05）（平均差异 = 0.405，95% CI = 0.2028至0.6080）。相关系数（r = 0.4721，p < 0.0001）提示正常组织和肿瘤组织中MLK4水平之间存在中度相关。结肠癌标本的RT-PCR分析显示MLK4 mRNA水平显著升高（p < 0.05）（平均差异 = 2.139，95% CI = 0.8789至3.400）。与低表达相比，高MLK4表达显示出总生存降低的趋势（HR = 1.25，log-rank p = 0.079）。同样，较高的MLK4甲基化在结肠腺癌患者中显示出总生存较差的趋势（HR = 1.54，95% CI 0.96-2.47；log-rank p = 0.07）。
结论：MLK4在结肠癌中转录和翻译水平上的表达升高提示其参与结肠肿瘤病理。MLK4激酶在细胞水平的表达及其与生存的相关性有助于阐明结肠癌发生的复杂本质，并识别未知的预后标志物。
查看英文原文 English abstract
Background: Mixed Lineage Kinase 4 (MLK4) is a protein kinase from the serine/threonine kinase family functioning through the MAPK pathway. The association of MLK4 with colon cancer oncologic outcomes has not been well described. We aimed to investigate the molecular expression of MLK4 at both the protein and mRNA levels, its differential expression across stages, and the association with survival in cases of increased expression using the TCGA databases.
Methods: An in-silico analysis of MLK4 in colorectal cancers was performed using the TCGA database for stage-wise expression and overall survival analysis in 288 patients. A TMA of colon cancer and matched adjacent normal colon tissue, annotated with survival data and clinical stage (AJCC 8th edition), was used to investigate differential expressions of MLK4 in colon cancer. Laser Capture microdissection was performed with FFPE samples consisting of normal tissue and tumor. MLK4 RNA was quantified using organic extraction and RT-PCR techniques.
Results: IHC of MLK4 in 74 matched sample pairs revealed a significant (p < 0.05) increase in MLK4 expression (mean difference = 0.405, 95% CI = 0.2028 to 0.6080) in colon cancer compared to normal tissue. The correlation coefficient (r = 0.4721, p < 0.0001) suggested a moderate correlation between MLK4 levels in normal and tumor tissues. RT-PCR analysis in colon cancer specimens revealed a significant (p<0.05) increase in mRNA levels of MLK4 (mean difference = 2.139, 95% CI = 0.8789 to 3.400). High MLK4 expression showed a trend toward reduced overall survival compared with low expression (HR = 1.25, log-rank p = 0.079). Similarly, higher MLK4 methylation demonstrated a trend toward poorer overall survival in colon adenocarcinoma patients (HR = 1.54, 95% CI 0.96-2.47; log-rank p = 0.07).
Conclusion: Increased expression of MLK4, both transcriptionally and translationally, in colon cancer suggests involvement in colon tumor pathology. Cellular-level expressions and correlations of MLK4 kinase with survival can help elucidate the complex nature of colon cancer development and identify unknown prognostic markers.
利益披露 Disclosure
N. Kumar, None..
H. Kapoor, None..
D. Allison, None..
G. Gantt, None.