Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Asian Pac J Cancer Prev. 2023 May 1;24(5):1571-1582. doi: 10.31557/APJCP.2023.24.5.1571.
Breast cancer (BC) is the most common malignancy in women worldwide. Altered miRNA profile can disturb the metabolic homeostatic via regulation of gene expression in BC.
In the present study to evaluate which miRNA, regulate metabolic pathways according to their stage, we performed comprehensive analysis of BC expression (mRNA and miRNA) of a set of patients by comparing samples of solid tumor tissue and adjacent tissue. The mRNA and miRNA data of breast cancer were downloaded from the cancer genome database (TCGA) using TCGAbiolinks package. Differentially expressed (mRNAs and miRNAs) was determined by DESeq2 package and predict valid miRNA-mRNA pairs using multiMiR package. All analyses were performed using the R software. Compound-reaction-enzyme-gene network was constructed using the Metscape a plugin for Cytoscape software. Then, core subnetwork computed by CentiScaPe, another plugin for Cytoscape.
In Stage I, hsa-miR-592, hsa-miR-449a and hsa-miR-1269a targeted HS3ST4, ACSL1 and USP9Y genes respectively. In stage II, hsa-miR-3662, Hsa-miR-429, and hsa-miR-1269a targeted GYS2, HAS3, ASPA, TRHDE, USP44, GDA, DGAT2, and USP9Y genes. In stage III, hsa-miR-3662 targeted TRHDE, GYS2, DPYS, HAS3, NMNAT2, ASPA genes. In stage IV, hsa-miR-429, has-miR-23c, and hsa-miR-449a targeted genes GDA, DGAT2, PDK4, ALDH1A2, ENPP2, and KL. Those miRNAs and their targets were identified as the discriminative elements for the four stages of breast cancer.
The most notable differences between BC and normal tissue in four stages involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., Amylose, N-acetyl-D-glucosamin, beta-D-Glucuronoside, ""g""-CEHC-glucuronide, ""a""-CEHC-glucuronide, Heparan-glucosamine, 5,6-Dihydrouracil, 5,6-Dihydrothymine), branch-chain amino acid metabolism (e.g., N-Acetyl-L-aspartate, N-Formyl-L-aspartate, N-acetyl-L-asparagine), Retinal metabolism (e.g., Retinal, 9-cis-retinal, 13-cis`-retinal) and (FAD, NAD) as central coenzymes of metabolism. Set of crucial microRNAs and targeted genes plus the related metabolites were introduced for four stages of BC that can be consider for therapeutic and diagnostic purposes in the different stages of disease.
乳腺癌（BC）是全世界女性中最常见的恶性肿瘤。miRNA 谱的改变可能通过调节 BC 中的基因表达来扰乱代谢稳态。
在本研究中，为了评估哪些 miRNA 根据其阶段调节代谢途径，我们通过比较实体瘤组织和相邻组织的一组患者的 BC 表达（mRNA 和 miRNA），进行了综合分析。使用 TCGAbiolinks 包从癌症基因组数据库（TCGA）下载乳腺癌的 mRNA 和 miRNA 数据。使用 DESeq2 包确定差异表达（mRNA 和 miRNA），并使用 multiMiR 包预测有效 miRNA-mRNA 对。所有分析均使用 R 软件进行。使用 Metscape 插件构建化合物-反应-酶-基因网络，然后使用 Cytoscape 软件的 CentiScaPe 插件构建核心子网。
在 I 期，hsa-miR-592、hsa-miR-449a 和 hsa-miR-1269a 分别靶向 HS3ST4、ACSL1 和 USP9Y 基因。在 II 期，hsa-miR-3662、Hsa-miR-429 和 hsa-miR-1269a 靶向 GYS2、HAS3、ASPA、TRHDE、USP44、GDA、DGAT2 和 USP9Y 基因。在 III 期，hsa-miR-3662 靶向 TRHDE、GYS2、DPYS、HAS3、NMNAT2 和 ASPA 基因。在 IV 期，hsa-miR-429、has-miR-23c 和 hsa-miR-449a 靶向 GDA、DGAT2、PDK4、ALDH1A2、ENPP2 和 KL 基因。这些 miRNA 及其靶标被鉴定为乳腺癌四个阶段的鉴别特征。
在四个阶段的 BC 与正常组织之间最显著的差异涉及多个途径和代谢物，包括：碳水化合物代谢（例如，支链淀粉、N-乙酰-D-氨基葡萄糖、β-D-葡萄糖醛酸苷、“g”-CEHC-葡糖苷酸、“a”-CEHC-葡糖苷酸、肝素葡糖胺、5,6-二氢尿嘧啶、5,6-二氢胸腺嘧啶）、支链氨基酸代谢（例如，N-乙酰-L-天冬氨酸、N-甲酰-L-天冬氨酸、N`-乙酰-L-天冬酰胺）、视网膜代谢（例如，视黄醛、9-顺式-视黄醛、13-顺式-视黄醛）和（FAD、NAD）作为代谢的中心辅酶。一组关键的 microRNAs 和靶向基因以及相关代谢物被引入到 BC 的四个阶段，可考虑用于疾病不同阶段的治疗和诊断目的。
