Analyses of our microRNA (miRNA) expression signature combined with The Cancer Genome Atlas (TCGA) data revealed that both strands of pre-miR-139(miR-139-5p, the guide strand, andmiR-139-3p, the passenger strand) are significantly downregulated in lung adenocarcinoma (LUAD) clinical specimens. Functional analyses of LUAD cells ectopically expressingmiR-139-3pshowed significant suppression of their aggressiveness (e.g., cancer cell proliferation, migration, and invasion). The involvement of the passenger strand,miR-139-3p, in LUAD pathogenesis, is an interesting finding contributing to the elucidation of unknown molecular networks in LUAD. Of 1108 genes identified asmiR-139-3ptargets in LUAD cells, 21 were significantly upregulated in LUAD tissues according to TCGA analysis, and their high expression negatively affected the prognosis of LUAD patients. We focused on thyroid hormone receptor interactor 13 (TRIP13) and investigated its cancer-promoting functions in LUAD cells. Luciferase assays showed thatmiR-139-3pdirectly regulated TRIP13. siRNA-mediatedTRIP13knockdown and TRIP13 inhibition by a specific inhibitor (DCZ0415) attenuated the malignant transformation of LUAD cells. Interestingly, when used in combination with anticancer drugs (cisplatin and carboplatin), DCZ0415 exerted synergistic effects on cell proliferation suppression. Identifying the molecular pathways regulated by tumor-suppressive miRNAs (including passenger strands) may aid in the discovery of diagnostic markers and therapeutic targets for LUAD.
结合我们自身建立的microRNA（miRNA）表达谱与癌症基因组图谱（TCGA）数据分析发现，在肺腺癌（LUAD）临床样本中，前体miR-139的双链（引导链miR-139-5p与随从链miR-139-3p）均呈现显著下调。对异位表达miR-139-3p的LUAD细胞进行功能分析显示，其侵袭性（包括癌细胞增殖、迁移和侵袭能力）受到显著抑制。随从链miR-139-3p参与LUAD发病机制的发现，为阐明LUAD中未知的分子网络提供了重要线索。在LUAD细胞中鉴定出的1108个miR-139-3p靶基因中，通过TCGA分析发现21个基因在LUAD组织中显著上调，且这些基因的高表达与LUAD患者不良预后相关。我们聚焦于甲状腺激素受体相互作用蛋白13（TRIP13），深入研究了其在LUAD细胞中的促癌功能。荧光素酶报告实验证实miR-139-3p可直接调控TRIP13。通过siRNA介导的TRIP13敲低及特异性抑制剂（DCZ0415）对TRIP13的抑制，均能有效减弱LUAD细胞的恶性表型。值得注意的是，DCZ0415与抗癌药物（顺铂和卡铂）联用时，在抑制细胞增殖方面表现出协同效应。揭示肿瘤抑制性miRNA（包括随从链）调控的分子通路，将有助于发现LUAD的诊断标志物与治疗靶点。
肿瘤(癌症)患者之家