BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Sci Rep. 2019 Jan 15;9(1):123. doi: 10.1038/s41598-018-36328-w.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of <8%. Its dismal prognosis stems from inefficient therapeutic modalities owing to the lack of understanding about pancreatic cancer pathogenesis. Considering the molecular complexity and heterogeneity of PDAC, identification of novel molecular contributors involved in PDAC onset and progression using global "omics" analysis will pave the way to improved strategies for disease prevention and therapeutic targeting. Meta-analysis of multiple miRNA microarray datasets containing healthy controls (HC), chronic pancreatitis (CP) and PDAC cases, identified 13 miRNAs involved in the progression of PDAC. These miRNAs showed dysregulation in both tissue as well as blood samples, along with progressive decrease in expression from HC to CP to PDAC. Gene-miRNA interaction analysis further elucidated 5 miRNAs (29a/b, 27a, 130b and 148a) that are significantly downregulated in conjunction with concomitant upregulation of their target genes throughout PDAC progression. Among these, miRNA-29a/b targeted genes were found to be most significantly altered in comparative profiling of HC, CP and PDAC, indicating its involvement in malignant evolution. Further, pathway analysis suggested direct involvement of miRNA-29a/b in downregulating the key pathways associated with PDAC development and metastasis including focal adhesion signaling and extracellular matrix organization. Our systems biology data analysis, in combination with real-time PCR validation indicates direct functional involvement of miRNA-29a in PDAC progression and is a potential prognostic marker and therapeutic candidate for patients with progressive disease.
胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，5 年生存率<8%。其预后不佳的原因是由于缺乏对胰腺癌发病机制的了解，导致治疗方法效率低下。鉴于 PDAC 的分子复杂性和异质性，使用全局“组学”分析鉴定参与 PDAC 发生和进展的新型分子贡献者，将为疾病预防和治疗靶向的改进策略铺平道路。对包含健康对照（HC）、慢性胰腺炎（CP）和 PDAC 病例的多个 miRNA 微阵列数据集的荟萃分析，确定了 13 个参与 PDAC 进展的 miRNA。这些 miRNA 在组织和血液样本中均表现出失调，并且随着从 HC 到 CP 再到 PDAC 的表达逐渐降低。基因-miRNA 相互作用分析进一步阐明了 5 个 miRNA（29a/b、27a、130b 和 148a）在整个 PDAC 进展过程中与靶基因的同时上调而显著下调。在这些 miRNA 中，miRNA-29a/b 的靶向基因在 HC、CP 和 PDAC 的比较分析中发现变化最显著，表明其参与了恶性演变。此外，途径分析表明 miRNA-29a/b 直接参与下调与 PDAC 发展和转移相关的关键途径，包括焦点粘附信号和细胞外基质组织。我们的系统生物学数据分析结合实时 PCR 验证表明 miRNA-29a 直接参与 PDAC 进展，是进展性疾病患者的潜在预后标志物和治疗候选物。
