Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.

中文翻译：

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抑制 miR-21 调节突变 KRAS 效应通路并阻止胰腺导管腺癌的发展


几乎所有胰腺导管腺癌 (PDA) 都是在 KRAS 激活后发生的，KRAS 激活会通过额外的转录和表观遗传调控触发上皮转化和促纤维增生基质的募集，但仅描述了其中的少数调控机制。我们从基因工程突变 KRAS 和 P53 (KPC) 小鼠中最早的癌前胰腺上皮内瘤变 (PanIN) 开始，对失调的 miRNA 进行了分析，这些小鼠被编程为重现人类 PDA 肿瘤发生。我们将 miR-21 和 miR-224 鉴定为 PanIN 和 PDA 中的细胞特异性和区室特异性调节因子。 miR-21 在癌前导管的肿瘤上皮细胞中过表达，而 miR-224 在 PDA 基质中的癌症相关成纤维细胞中过表达。抑制 miR-21 可将促肿瘤功能恢复至基线水平。 miR-224 的过度表达诱导正常成纤维细胞激活表型。体内 miR-21 抑制提高了已建立的 PDA 的存活率。重要的是，早期全身性 miR-21 抑制完全阻止了癌前进展。最后，对癌症基因组图谱 PDA 队列中 miR-21 表达的评估确定了人类肿瘤中肿瘤上皮细胞含量与 miR-21 表达之间的相关性，为进行人类研究提供了进一步的理论基础。因此，miR-21可能有助于早期PanIN检测，并可用于拦截正在发展的胰腺癌前病变和其他KRAS驱动的癌前病变。