PDF(Pubmed)
Abstract：
Background: Colon adenocarcinoma (COAD) has increasing incidence and is one of the most common malignant tumors. The mitochondria involved in cell energy metabolism, oxygen free radical generation, and cell apoptosis play important roles in tumorigenesis and progression. The relationship between mitochondrial genes and COAD remains largely unknown. Methods: COAD data including 512 samples were set out from the UCSC Xena database. The nuclear mitochondrial-related genes (NMRGs)-related risk prognostic model and prognostic nomogram were constructed, and NMRGs-related gene mutation and the immune environment were analyzed using bioinformatics methods. Then, a liver metastasis model of colorectal cancer was constructed and protein expression was detected using Western blot assay. Results: A prognostic model for COAD was constructed. Comparing the prognostic model dataset and the validation dataset showed considerable correlation in both risk grouping and prognosis. Based on the risk score (RS) model, the samples of the prognostic dataset were divided into high risk group and low risk group. Moreover, pathologic N and T stage and tumor recurrence in the two risk groups were significantly different. The four prognostic factors, including age and pathologic T stage in the nomogram survival model also showed excellent predictive performance. An optimal combination of nine differentially expressed NMRGs was finally obtained, including LARS2, PARS2, ETHE1, LRPPRC, TMEM70, AARS2, ACAD9, VARS2, and ATP8A2. The high-RS group had more inflamed immune features, including T and CD4+ memory cell activation. Besides, mitochondria-associated LRPPRC and LARS2 expression levels were increased in vivo xenograft construction and liver metastases assays. Conclusion: This study established a comprehensive prognostic model for COAD, incorporating nine genes associated with nuclear-mitochondrial functions. This model demonstrates superior predictive performance across four prognostic factors: age, pathological T stage, tumor recurrence, and overall prognosis. It is anticipated to be an effective model for enhancing the prognosis and treatment of COAD.
摘要：
背景:结肠腺癌(COAD)是最常见的恶性肿瘤之一,发病率日益增高。参与细胞能量代谢的线粒体，氧自由基的产生，细胞凋亡在肿瘤发生和发展中起着重要作用。线粒体基因与COAD之间的关系仍然未知。方法：从UCSCXena数据库中列出包含512个样本的COAD数据。构建核线粒体相关基因(NMRGs)相关风险预后模型和预后列线图,并利用生物信息学方法对NMRGs相关基因突变和免疫环境进行分析。然后，构建结直肠癌肝转移模型,采用Westernblot法检测蛋白表达.结果:建立了COAD的预后模型。比较预后模型数据集和验证数据集在风险分组和预后方面显示出相当大的相关性。基于风险评分(RS)模型，将预后数据集的样本分为高危组和低危组.此外，两个危险组的病理N和T分期以及肿瘤复发差异显著。四个预后因素，在列线图生存模型中包括年龄和病理T分期也显示出优异的预测性能.最终获得了9个差异表达的NMRGs的最优组合，包括LARS2，PARS2，ETHE1，LRPPRC，TMEM70、AARS2、ACAD9、VARS2和ATP8A2。高RS组的免疫功能更加发炎，包括T和CD4+记忆细胞激活。此外,线粒体相关的LRPPRC和LARS2表达水平在体内异种移植物构建和肝转移试验中增加。结论:本研究建立了COAD的综合预后模型,整合了9个与核线粒体功能相关的基因。该模型在四个预后因素中表现出卓越的预测性能：年龄、病理T分期,肿瘤复发,和总体预后。有望成为提高COAD预后和治疗效果的有效模型。
