Eskandarion Mohammad Reza, Eskandarieh Sharareh, Shakoori Farahani Abbas, Mahmoodzadeh Habibollah, Shahi Farhad, Oghabian Mohammad Ali, Shirkoohi Reza
Cancer Research Center, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran.
Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Heliyon. 2024 Apr 25;10(9):e30253. doi: 10.1016/j.heliyon.2024.e30253. eCollection 2024 May 15.
BACKGROUND & AIM: The histologic and molecular changes from intestinal metaplasia (IM) to gastric cancer (GC) have not been fully characterized. The present study sought to identify potential alterations in signaling pathways in IM and GC to predict disease progression; these alterations can be considered therapeutic targets.
MATERIALS & METHODS: Seven gene expression profiles were selected from the GEO database. Discriminate differentially expressed genes (DEGs) were analyzed by EnrichR. The STRING database, Cytoscape, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, NetworkAnalyst, MirWalk database, OncomiR, and bipartite miRNA‒mRNA correlation network was used for downstream analyses of selected module genes.
Analyses revealed that extracellular matrix-receptor interactions (ITGB1, COL1A1, COL1A2, COL4A1, FN1, COL6A3, and THBS2) in GC and PPAR signaling pathway interactions (FABP1, APOC3, APOA1, HMGCS2, and PPARA and PCK1) in IM may play key roles in both the carcinogenesis and progression of underlying GC from intestinal metaplasia. IM enrichment indicated that this is closely related to digestion and absorption. The TF-hub gene regulatory network revealed that AR, TCF4, SALL4, and ESR1 were more important for hub gene expression. It was revealed that the development and prediction of GC may be affected by hsa-miR-29. It was found that PTGR1, C1orf115, CRYL1, ALDOB, and SULT1B1 were downregulated in GC and upregulated in IM. Therefore, they might have tumor suppressor activity in GC progression.
New potential biomarkers and pathways involved in GC and IM were identified that are important for the transformation of GC from IM to adenocarcinoma and can be therapeutic targets for GC.
从肠化生（IM）到胃癌（GC）的组织学和分子变化尚未完全明确。本研究旨在确定IM和GC信号通路中的潜在改变，以预测疾病进展；这些改变可被视为治疗靶点。
从基因表达综合数据库（GEO数据库）中选取了7个基因表达谱。通过EnrichR分析鉴别差异表达基因（DEGs）。利用STRING数据库、Cytoscape、基因表达谱交互分析（GEPIA）、cbioportal、NetworkAnalyst、MirWalk数据库、OncomiR和二分miRNA-mRNA相关网络对选定模块基因进行下游分析。
分析显示，GC中的细胞外基质-受体相互作用（整合素β1、Ⅰ型胶原α1链、Ⅰ型胶原α2链、Ⅳ型胶原α1链、纤连蛋白1、Ⅵ型胶原α3链和血小板反应蛋白2）以及IM中的过氧化物酶体增殖物激活受体（PPAR）信号通路相互作用（脂肪酸结合蛋白1、载脂蛋白C3、载脂蛋白A1、3-羟基-3-甲基戊二酰辅酶A合成酶2、PPARα和磷酸烯醇式丙酮酸羧激酶1）可能在IM引发GC的癌变及进展过程中起关键作用。IM富集表明这与消化吸收密切相关。转录因子-枢纽基因调控网络显示，雄激素受体、转录因子4、锌指蛋白SALL4和雌激素受体1对枢纽基因表达更为重要。结果表明，hsa-miR-29可能影响GC的发生发展及预测。研究发现，前列腺素还原酶1、1号染色体开放阅读框115、富含半胱氨酸的分泌蛋白1、醛缩酶B和磺基转移酶1B1在GC中表达下调，在IM中表达上调。因此，它们可能在GC进展中具有肿瘤抑制活性。
确定了与GC和IM相关的新的潜在生物标志物和信号通路，这些对于GC从IM转变为腺癌具有重要意义，并且可成为GC的治疗靶点。
