Department of Gastroenterology, Zhongshan Hospital Affiliated to Fudan University, NO. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China.
Department of Radiation Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032, People's Republic of China.
Cell Death Dis. 2022 Mar 14;13(3):237. doi: 10.1038/s41419-022-04692-1.
Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25.
溶质载体家族 25（SLC25）在人线粒体膜上编码转运蛋白，作为代谢物的载体发挥作用。虽然 SLC25 遗传变异与人类代谢疾病相关，但它们在结肠癌中的作用尚不清楚。从癌症基因组图谱中检索结肠癌病例，并鉴定 SLC25 的转录差异表达成员（DEMs）。还研究了 DNA 水平的改变、临床病理特征和临床生存情况。基于 DEMs 构建了风险评分模型，以进一步评估其在临床环境中的预后价值。使用来自基因表达综合数据库的数据集的生物信息学分析、临床标本的免疫组织化学评估以及结肠癌衍生细胞系的功能实验对结果进行了初步验证。在 SLC25 的 53 个成员中鉴定出 37 个 DEMs。使用集成 LASSO 回归和多变量 Cox 回归将 37 个 DEMs 中的 8 个引入风险评分模型。通过 GSE395282 和 GSE175356 验证，具有高风险评分的 DEMs 与肿瘤免疫浸润增加和糖酵解和凋亡含量减少的表型相关。SLC25A5 在癌症中下调，其上调与公共数据集和临床病例中患者的总体生存率提高相关。在接受手术治疗的 79 名患者中，高 SLC25A5 表达是独立的预后因素。在 106 名晚期结肠癌患者的标本中，确定了 CD8 和 SLC25A5 之间的负相关。SLC25A5 抑制 MAPK 信号通路，抑制细胞增殖，上调程序性细胞死亡相关标志物的表达，发挥其生物学功能。我们的研究表明，线粒体 SLC25 在结肠癌患者中有预后价值。通过随后的原位和体外验证的生物信息学分析为进一步研究 SLC25 鉴定成员的功能和机制提供了方向。
