PO.MCB10.01 · 分子与细胞生物学
miR-1293通过靶向新型S100A16-Hippo-EMT轴抑制弥漫性胸膜间皮瘤生长
miR-1293 suppresses diffuse pleural mesothelioma growth by targeting a novel S100A16-Hippo-EMT axis
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摘要 Abstract
中文摘要
背景：弥漫性胸膜间皮瘤（DPM）以频繁的NF2缺失、Hippo通路破坏和有限的治疗手段为特征。我们鉴定出miR-1293是一种抑癌性miRNA，可靶向以S100A16为中心、涉及Hippo/YAP和上皮-间质转化（EMT）的Hippo/EMT轴。方法：我们在多个DPM细胞系中进行了高通量人miRNA模拟物筛选并结合增殖实验，以鉴定抗肿瘤miRNA。通过qRT-PCR检测DPM肿瘤和正常胸膜中miR-1293的表达。通过biotin-miR-1293下拉结合RNA-seq及计算机预测来定位靶标，随后与通路和DepMap数据整合，以定义一个S100A16-Hippo/EMT模块。在NF2野生型和NF2/Hippo缺陷型DPM细胞系中，以及在MB52异种移植模型中，采用基于局部水凝胶的（SFH-miR-1293）递送于皮下和原位胸膜模型，检测了miR-1293再表达的功能效应。结果：筛选鉴定出miR-1293为最具抗增殖活性的miRNA，且miR-1293在DPM中相较正常胸膜显著低表达。在miR-1293低表达的DPM细胞系中再表达可降低增殖、集落和软琼脂生长，对非恶性间皮细胞影响极小，并诱导凋亡和细胞周期阻滞。靶标定位得到345个基因，富集于Hippo信号和EMT，另有mTORC1、IL-2/STAT5和缺氧特征，以及一个19基因的核心S100A16-Hippo-EMT模块。在该模块中，S100A16是最必需且预后不良作用最强的基因，在NF2/Hippo缺陷型细胞系（H2052、MB52、MB24）中高表达，伴有YAP/TAZ/TEAD激活和EMT样特征。miR-1293再表达优先损害这些NF2/Hippo缺陷型细胞的活力和克隆形成能力，并协调抑制S100A16、YAP/TAZ/TEAD和EMT标志物。在体内，SFH-miR-1293显著降低肿瘤负荷、Ki-67和生物发光，增加裂解型caspase-3，并在异种移植和原位胸膜模型中延长生存期。结论：miR-1293是DPM中的一种抑癌性miRNA，可靶向S100A16-Hippo-EMT轴，并在NF2/Hippo缺陷型间皮瘤中显示优先活性。基于局部水凝胶的递送在体内引发强大的抗肿瘤效应，支持将miR-1293作为DPM的治疗候选物，以及作为Hippo/YAP导向和免疫治疗策略的合理搭档。
查看英文原文 English abstract
Background: Diffuse pleural mesothelioma (DPM) features frequent NF2 loss, Hippo pathway disruption, and limited therapies. We identify miR-1293 as a tumor-suppressive miRNA that targets an S100A16-centered Hippo/EMT axis involving Hippo/YAP and epithelial-mesenchymal transition (EMT) in DPM. Methods: We performed a high-throughput human miRNA mimic screen across multiple DPM cell lines with proliferation assays to identify anti-tumor miRNAs. miR-1293 expression was measured by qRT-PCR in DPM tumors and normal pleura. Targets were mapped by biotin-miR-1293 pulldown plus RNA-seq and in silico prediction, then integrated with pathway and DepMap data to define an S100A16-Hippo/EMT module. Functional effects of miR-1293 re-expression were tested in NF2-wild-type and NF2/Hippo-deficient DPM lines and in MB52 xenografts using local hydrogel-based (SFH-miR-1293) delivery in subcutaneous and orthotopic pleural models. Results: The screen identified miR-1293 as a top antiproliferative miRNA, and miR-1293 was significantly underexpressed in DPM versus normal pleura. Re-expression in miR-1293-low DPM lines reduced proliferation, colony and soft-agar growth, with minimal impact on non-malignant mesothelial cells, and induced apoptosis and cell-cycle arrest. Target mapping yielded 345 genes enriched for Hippo signaling and EMT, with additional mTORC1, IL-2/STAT5, and hypoxia signatures, and a 19-gene core S100A16-Hippo-EMT module. Within this module, S100A16 was the most essential and strongest adverse prognostic gene, highly expressed in NF2/Hippo-deficient lines (H2052, MB52, MB24) with activated YAP/TAZ/TEAD and EMT-like features. miR-1293 re-expression preferentially impaired viability and clonogenicity in these NF2/Hippo-deficient cells, with coordinated suppression of S100A16, YAP/TAZ/TEAD, and EMT markers. In vivo, SFH-miR-1293 significantly reduced tumor burden, Ki-67, and bioluminescence, increased cleaved caspase-3, and prolonged survival in xenograft and orthotopic pleural models. Conclusions: miR-1293 is a tumor-suppressive miRNA in DPM that targets an S100A16-Hippo-EMT axis and shows preferential activity in NF2/Hippo-deficient mesothelioma. Local hydrogel-based delivery elicits strong antitumor effects in vivo, supporting miR-1293 as a therapeutic candidate for DPM and a rational partner for Hippo/YAP-directed and immunotherapy strategies.
利益披露 Disclosure
V. Singh, None.