Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function II. Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function II

Several miRNAs have tissue-specific patterns consistent with crucial functions in many biological processes and are candidate biomarkers of disease. Yet, there is limited knowledge about the role of pancreas-specific miRNAs in pancreatic pathologies. Here, we show that miR-216a is a conserved, pancreas-specific miRNA with important roles in pancreatic islet and acinar cells. By profiling miRNAs from human islets and subsequent systematic tissue analysis we found that miR-216a is highly enriched in endocrine and exocrine pancreas. Deletion of miR-216a in mice lead to a reduction in islet size, β-cell mass and insulin levels. RNA-sequencing indicated that cell cycle and proliferation were the most significantly regulated biological processes in miR-216 knockout pancreata. miR-216a was induced by TGF-β signalling and inhibition of miR-216a increased apoptosis and decreased cell proliferation in both β- and exocrine cells. Deletion of miR-216a in the pancreatic cancer prone mouse line Kras G12D ;Ptf1a CreER reduced the propensity of pancreatic cancer precursor lesions. Notably, circulating miR-216a levels were elevated in both mice and humans with pancreatic cancer. Collectively, our study gives insights into how β-cell mass and acinar cell growth are modulated by a pancreas-specific miRNA but also suggests miR-216a as a promising biomarker for diagnosis of pancreatic diseases. Overall design: Six bulk RNA sequencing profiles from whole pancreas of 1 day old wild type (WT) and miR216a-/- mice

多种微小RNA（miRNA）具有组织特异性表达模式，该模式与其在诸多生物学过程中发挥的关键功能相契合，同时可作为疾病的候选生物标志物。然而，目前对于胰腺特异性微小RNA在胰腺病变中的作用尚缺乏深入认知。本研究证实，miR-216a是一种保守的胰腺特异性微小RNA，在胰岛与腺泡细胞中发挥重要功能。通过对人源胰岛的微小RNA进行表达谱分析，并后续开展系统性组织检测，我们发现miR-216a高度富集于内分泌胰腺与外分泌胰腺。在小鼠体内敲除miR-216a，会导致胰岛体积、β细胞质量及胰岛素水平下降。RNA测序结果显示，细胞周期与细胞增殖是miR-216a敲除胰腺中受调控最为显著的生物学过程。转化生长因子β（TGF-β）信号通路可诱导miR-216a的表达；抑制miR-216a则会增加β细胞与外分泌细胞的凋亡率，并降低其细胞增殖能力。在胰腺癌易感小鼠品系Kras G12D;Ptf1a CreER中敲除miR-216a，可降低胰腺癌前驱病变的发生倾向。值得注意的是，胰腺癌患者与模型小鼠的循环miR-216a水平均显著升高。综上，本研究不仅揭示了胰腺特异性微小RNA如何调控β细胞质量与腺泡细胞生长，同时还表明miR-216a可作为胰腺疾病诊断的潜在候选生物标志物。实验设计概述：对1日龄野生型（WT）与miR216a敲除（miR216a-/-）小鼠的全胰腺组织开展了6组批量RNA测序分析。