Department of Healthcare Biotechnology, Atta ur Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H12, Islamabad, Islamabad Capital Territory, Pakistan.
PLoS One. 2023 Aug 9;18(8):e0289839. doi: 10.1371/journal.pone.0289839. eCollection 2023.
The bidirectional causal relationship between type 2 diabetes mellitus (T2DM) and breast cancer (BC) has been established by numerous epidemiological studies. However, the underlying molecular mechanisms are not yet fully understood. Identification of hub genes implicated in T2DM-BC molecular crosstalk may help elucidate on the causative mechanisms. For this, expression series GSE29231 (T2DM-adipose tissue), GSE70905 (BC- breast adenocarcinoma biopsies) and GSE150586 (diabetes and BC breast biopsies) were extracted from Gene Expression Omnibus (GEO) database, and analyzed to obtain differentially expressed genes (DEGs). The overlapping DEGs were determined using FunRich. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Transcription Factor (TF) analyses were performed on EnrichR software and a protein-protein interaction (PPI) network was constructed using STRING software. The network was analyzed on Cytoscape to determine hub genes and Kaplan-Meier plots were obtained. A total of 94 overlapping DEGs were identified between T2DM and BC samples. These DEGs were mainly enriched for GO terms RNA polymerase II core promoter proximal region sequence and its DNA binding, and cAMP response element binding protein, and KEGG pathways including bladder cancer, thyroid cancer and PI3K-AKT signaling. Eight hub genes were identified: interleukin 6 (IL6), tumor protein 53 (TP53), interleukin 8 (CXCL8), MYC, matrix metalloproteinase 9 (MMP9), beta-catenin 1 (CTNNB1), nitric oxide synthase 3 (NOS3) and interleukin 1 beta (IL1β). MMP9 and MYC associated unfavorably with overall survival (OS) in breast cancer patients, IL6, TP53, IL1β and CTNNB1 associated favorably, whereas NOS3 did not show any correlation with OS. Salt inducible kinase 1 (SIK1) was identified as a significant key DEG for comorbid samples when compared with BC, also dysregulated in T2DM and BC samples (adjusted p <0.05). Furthermore, four of the significant hub genes identified, including IL6, CXCL8, IL1B and MYC were also differentially expressed for comorbid samples, however at p < 0.05. Our study identifies key genes including SIK1, for comorbid state and 8 hub genes that may be implicated in T2DM-BC crosstalk. However, limitations associated with the insilico nature of this study necessitates for subsequent validation in wet lab. Hence, further investigation is crucial to study the molecular mechanisms of action underlying these genes to fully explore their potential as diagnostic and prognostic biomarkers and therapeutic targets for T2DM-BC association.
2 型糖尿病（T2DM）和乳腺癌（BC）之间的双向因果关系已被许多流行病学研究证实。然而，其潜在的分子机制尚不完全清楚。确定参与 T2DM-BC 分子相互作用的枢纽基因可能有助于阐明因果机制。为此，从基因表达综合数据库（GEO）中提取了表达系列 GSE29231（T2DM-脂肪组织）、GSE70905（BC-乳腺腺癌活检）和 GSE150586（糖尿病和 BC 乳腺活检），并进行分析以获得差异表达基因（DEG）。使用 FunRich 确定重叠的 DEG。使用 EnrichR 软件对基因本体论（GO）、京都基因与基因组百科全书（KEGG）和转录因子（TF）分析进行分析，并使用 STRING 软件构建蛋白质-蛋白质相互作用（PPI）网络。在 Cytoscape 上分析网络以确定枢纽基因并获得 Kaplan-Meier 图。在 T2DM 和 BC 样本之间确定了 94 个重叠的 DEG。这些 DEG 主要富集在 RNA 聚合酶 II 核心启动子近端序列及其 DNA 结合和 cAMP 反应元件结合蛋白，以及膀胱癌、甲状腺癌和 PI3K-AKT 信号通路等 KEGG 途径。确定了 8 个枢纽基因：白细胞介素 6（IL6）、肿瘤蛋白 53（TP53）、白细胞介素 8（CXCL8）、MYC、基质金属蛋白酶 9（MMP9）、β-连环蛋白 1（CTNNB1）、一氧化氮合酶 3（NOS3）和白细胞介素 1β（IL1β）。MMP9 和 MYC 与乳腺癌患者的总生存期（OS）不良相关，IL6、TP53、IL1β 和 CTNNB1 与 OS 相关，而 NOS3 与 OS 无相关性。与 BC 相比，当比较合并样本时，盐诱导激酶 1（SIK1）被鉴定为重要的关键 DEG，并且在 T2DM 和 BC 样本中也失调（调整后的 p <0.05）。此外，在所确定的 8 个枢纽基因中，包括 IL6、CXCL8、IL1B 和 MYC 在内的 4 个基因在合并样本中也表现出差异表达，但 p <0.05。我们的研究确定了关键基因，包括 SIK1，用于合并状态和 8 个枢纽基因，这些基因可能与 T2DM-BC 相互作用有关。然而，由于本研究的计算性质所带来的局限性，需要在湿实验室进行后续验证。因此，进一步的研究对于研究这些基因的作用机制至关重要，以充分探索它们作为 T2DM-BC 关联的诊断和预后生物标志物和治疗靶点的潜力。
