School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Int J Mol Sci. 2021 Apr 15;22(8):4105. doi: 10.3390/ijms22084105.
The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.
卵巢低恶性潜能（LMP）肿瘤或交界性卵巢肿瘤（BOT）的发病机制和分子机制尚未完全阐明。迄今为止，手术仍然是治疗这种疾病的基石，诊断主要通过组织病理学进行。然而，目前还没有综合分析利用公开的实验数据来研究 BOT 的肿瘤发生。因此，我们首先利用基于功能组学的推测模型，从可获得的聚集数据集中，通过分析功能规律模式和对单独的基因集进行聚类，来探索所有 BOT 以及两种主要的 BOT 亚型，浆液性 BOT（SBOT）和黏液性 BOT（MBOT）之间的表达谱数据。接下来，我们预测并组装了这些靶向生物分子功能与其相关基因之间的关联。我们的研究发现，通过对所有 BOT、SBOT 和 MBOT 之间的多基因综合分析，可以通过基因表达谱准确识别 BOT；结果显示出前 41 个常见失调的生物分子功能，这些功能被分为四大类：免疫和炎症反应相关功能、细胞膜和转运蛋白相关功能、细胞周期和信号相关功能以及细胞代谢相关功能，这些都是其发病机制中的关键因素。与之前的研究相比，我们从上述分类类别中确定了 19 个有代表性的基因（免疫和炎症反应相关功能的 IL6、CCR2；细胞膜和转运蛋白相关功能的 IFNG、ATP1B1、GAS6 和 PSEN1；细胞周期和信号相关功能的 CTNNB1、GATA3 和 IL1B；细胞代谢相关功能的 AKT1、SIRT1、IL4、PDGFB、MAPK3、SRC、TWIST1、TGFB1、ADIPOQ 和 PPARGC1A），这些基因与 BOT 的发生和发展有关。我们还注意到，在所有 BOT、SBOT 和 MBOT 的分析基因集数据库的经典途径中，发生了半乳糖分解代谢途径的功能障碍。通过免疫染色，我们验证了 BOT 中白细胞介素 6（IL6）和半乳糖-1-磷酸尿苷酰转移酶（GALT）的表达显著高于对照组。总之，本研究构建了一个基于基因集整合分子功能组和生物物理途径的生物信息学平台，以解释 BOT 复杂的发病途径，这些重要发现表明免疫功能组失调和代谢途径功能障碍可能在 BOT 的肿瘤发生中起作用，并且可能有助于未来 BOT 的诊断和治疗。
