Fernandez-Castañer Elena, Vila-Casadesus Maria, Vila-Navarro Elena, Parra Carolina, Lozano Juan Jose, Castells Antoni, Gironella Meritxell
Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)/Hospital Clínic of Barcelona/Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain.
Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Catalonia, Spain.
Cancers (Basel). 2021 May 14;13(10):2369. doi: 10.3390/cancers13102369.
Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue ( = 3) and IPMN lesions ( = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients ( = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues ( = 4 Healthy; = 3 IPMN; = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC.
导管内乳头状黏液性肿瘤（IPMN）是一种胰腺囊性病变，可发展为胰腺导管腺癌（PDAC）。尽管IPMN的诊断发病率在不断上升，但其形成机制以及向浸润性癌进展的机制仍不清楚。微小RNA（miRNA）是小的非编码RNA，是mRNA翻译的抑制因子，也是IPMN和PDAC很有前景的诊断生物标志物。关于早期改变的miRNA在此过程中作用的功能信息，将为追踪IPMN向PDAC的进展提供新策略。为了检测IPMN中可能受miRNA调控的mRNA，我们将来自正常胰腺组织（n = 3）和IPMN病变组织（n = 4）的全转录组和miR组数据进行合并，并使用miRComb R包根据负相关和miRNA靶标预测数据库进行筛选。与PDAC数据的进一步比较分析使我们获得了在IPMN和PDAC中共享的miRNA-mRNA对的一个子集。功能富集分析揭示了主要与细胞结构、肌动蛋白细胞骨架和代谢相关的过程。MiR-181a似乎是这些过程的主要调节因子。通过qRT-PCR在一个独立的患者队列（n = 40）中验证了所选miRNA-mRNA对的表达，然后在不同的胰腺细胞系中进行分析。最后，我们构建了一个稳定过表达miR-181a的HPDE细胞的细胞模型，该模型显示肌动蛋白细胞骨架结构有显著改变，同时EPB41L4B和SEL1L的表达显著下调。我们还对胰腺组织（4例健康组织；3例IPMN；4例PDAC）进行了miR-181a的原位杂交以及EPB41L4B和SEL1L的免疫组织化学检测。在本研究中，我们深入探讨了miRNA改变在调节胰腺细胞在IPMN形成过程中经历并在PDAC中持续存在的结构和代谢变化方面的潜在影响。
