Biomarkers and effective therapeutic agents to improve the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) are urgently required. We aimed to analyze the prognostic value and mechanistic action of miR-93 in PDAC. Correlation of miR-93 tumor levels from 83 PDAC patients and overall survival (OS) was analyzed by Kaplan-Meier. MiR-93 depletion in PANC-1 and MIA PaCa-2 cells was achieved by CRISPR/Cas9 and miR-93 overexpression in HPDE cells by retroviral transduction. Cell proliferation, migration and invasion, cell cycle analysis, and in vivo tumor xenografts in nude mice were assessed. Proteomic analysis by mass spectrometry and western-blot was also performed. Finally, miR-93 direct binding to candidate mRNA targets was evaluated by luciferase reporter assays. High miR-93 tumor levels are significantly correlated with a worst prognosis in PDAC patients. MiR-93 abolition altered pancreatic cancer cells phenotype inducing a significant increase in cell size and a significant decrease in cell invasion and proliferation accompanied by a G2/M arrest. In vivo, lack of miR-93 significantly impaired xenograft tumor growth. Conversely, miR-93 overexpression induced a pro-tumorigenic behavior by significantly increasing cell proliferation, migration, and invasion. Proteomic analysis unveiled a large group of deregulated proteins, mainly related to G2/M phase, microtubule dynamics, and cytoskeletal remodeling. CRMP2, MAPRE1, and YES1 were confirmed as direct targets of miR-93. MiR-93 exerts oncogenic functions by targeting multiple genes involved in microtubule dynamics at different levels, thus affecting the normal cell division rate. MiR-93 or its direct targets (CRMP2, MAPRE1, or YES1) are new potential therapeutic targets for PDAC.

中文翻译：

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MiR-93与胰腺癌的不良预后有关，并通过靶向微管动力学来促进肿瘤进展。

迫切需要生物标志物和有效的治疗剂来改善胰腺导管腺癌（PDAC）的不良预后。我们旨在分析miR-93在PDAC中的预后价值和机制作用。Kaplan-Meier分析了83名PDAC患者的miR-93肿瘤水平与总生存期（OS）的相关性。通过逆转录病毒转导，CRISPR / Cas9和miDE-93在HPDE细胞中的过表达实现了PANC-1和MIA PaCa-2细胞中的MiR-93耗竭。评估裸鼠中的细胞增殖，迁移和侵袭，细胞周期分析以及体内肿瘤异种移植。还进行了通过质谱和蛋白质印迹的蛋白质组学分析。最后，通过荧光素酶报告基因分析评估了miR-93与候选mRNA目标的直接结合。高miR-93肿瘤水平与PDAC患者的最坏预后显着相关。MiR-93的取消改变了胰腺癌细胞的表型，导致细胞大小显着增加，细胞侵袭和增殖显着降低，并伴有G2 / M停滞。在体内，缺乏miR-93会严重损害异种移植肿瘤的生长。相反，miR-93的过表达通过显着增加细胞增殖，迁移和侵袭而诱导了促肿瘤发生行为。蛋白质组学分析揭示了一大堆失调的蛋白质，主要与G2 / M期，微管动力学和细胞骨架重塑有关。CRMP2，MAPRE1和YES1被确认为miR-93的直接靶标。MiR-93通过以不同水平靶向涉及微管动力学的多个基因来发挥致癌作用，从而影响正常细胞分裂率。MiR-93或其直接靶标（CRMP2，MAPRE1或YES1）是PDAC的新潜在治疗靶标。