DataSheet_1_Identification of the Shared Gene Signatures and Biological Mechanism in Type 2 Diabetes and Pancreatic Cancer.docx

BackgroundThe relationship between pancreatic cancer (PC) and type 2 diabetes mellitus (T2DM) has long been widely recognized, but the interaction mechanisms are still unknown. This study was aimed to investigate the shared gene signatures and molecular processes between PC and T2DM.
MethodsThe Gene Expression Omnibus (GEO) database was used to retrieve the RNA sequence and patient information of PC and T2DM. Weighted gene co-expression network analysis (WGCNA) was performed to discover a co-expression network associated with PC and T2DM. Enrichment analysis of shared genes present in PC and T2DM was performed by ClueGO software. These results were validated in the other four cohorts based on differential gene analysis. The predictive significance of S100A6 in PC was evaluated using univariate and multivariate Cox analyses, as well as Kaplan–Meier plots. The biological process of S100A6 enrichment in PC was detected using Gene Set Enrichment Analysis (GSEA). The involvement of S100A6 in the tumor immune microenvironment (TIME) was assessed by CIBERSORT. In vitro assays were used to further confirm the function of S100A6 in PC.
ResultsWGCNA recognized three major modules for T2DM and two major modules for PC. There were 44 shared genes identified for PC and T2DM, and Gene Ontology (GO) analysis showed that regulation of endodermal cell fate specification was primarily enriched. In addition, a key shared gene S100A6 was derived in the validation tests. S100A6 was shown to be highly expressed in PC compared to non-tumor tissues. PC patients with high S100A6 expression had worse overall survival (OS) than those with low expression. GSEA revealed that S100A6 is involved in cancer-related pathways and glycometabolism-related pathways. There is a strong relationship between S100A6 and TIME. In vitro functional assays showed that S100A6 helped to induce the PC cells’ proliferation and migration. We also proposed a diagram of common mechanisms of PC and T2DM.
ConclusionsThis study firstly revealed that the regulation of endodermal cell fate specification may be common pathogenesis of PC and T2DM and identified S100A6 as a possible biomarker and therapeutic target for PC and T2DM patients.

Background 胰腺癌（pancreatic cancer, PC）与2型糖尿病（type 2 diabetes mellitus, T2DM）之间的关联早已得到广泛认可，但其相互作用的分子机制仍未阐明。本研究旨在探讨胰腺癌与2型糖尿病共有的基因特征及分子进程。
Methods 本研究借助基因表达综合数据库（Gene Expression Omnibus, GEO）检索胰腺癌与2型糖尿病患者的RNA测序数据及临床信息。采用加权基因共表达网络分析（Weighted Gene Co-expression Network Analysis, WGCNA）构建与胰腺癌、2型糖尿病相关的共表达网络。通过ClueGO软件对胰腺癌与2型糖尿病共有的差异基因进行富集分析。基于差异基因分析，在另外4个队列中对上述结果进行验证。采用单因素、多因素Cox回归分析以及Kaplan–Meier生存曲线评估S100A6对胰腺癌的预测价值。通过基因集富集分析（Gene Set Enrichment Analysis, GSEA）探究S100A6在胰腺癌中的富集生物学过程。借助CIBERSORT算法分析S100A6与肿瘤免疫微环境（tumor immune microenvironment, TIME）的关联。通过体外实验进一步验证S100A6在胰腺癌中的功能。
Results 加权基因共表达网络分析分别筛选出2型糖尿病相关的3个关键模块与胰腺癌相关的2个关键模块。本研究共鉴定出44个胰腺癌与2型糖尿病的共有差异基因，基因本体（Gene Ontology, GO）富集分析显示，这些基因主要富集于内胚层细胞命运特化调控通路。此外，验证实验筛选得到关键共有基因S100A6。相较于正常组织，S100A6在胰腺癌组织中呈高表达。S100A6高表达的胰腺癌患者总体生存期（overall survival, OS）显著低于低表达患者。基因集富集分析结果显示，S100A6参与癌症相关通路及糖代谢相关通路。S100A6与肿瘤免疫微环境存在紧密关联。体外功能实验证实，S100A6可促进胰腺癌细胞的增殖与迁移。本研究还提出了胰腺癌与2型糖尿病共有的潜在作用机制示意图。
Conclusions 本研究首次揭示内胚层细胞命运特化调控可能是胰腺癌与2型糖尿病共有的发病机制，并鉴定出S100A6可作为胰腺癌与2型糖尿病患者潜在的生物标志物及治疗靶点。