Objective To investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target. Design FLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases. Results FLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis. Conclusions Based on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.

中文翻译：

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FLANC，一种新型灵长类特异性长链非编码 RNA 在结直肠癌中的治疗潜力

目的 研究一种名为 FLANC 的新型灵长类特异性长链非编码 RNA (lncRNA)，基于其基因组位置（与 pyknon 基序共定位）的功能，并表征其作为生物标志物和治疗靶点的潜力。在来自四个队列的 349 个肿瘤中分析了设计 FLANC 表达并与临床数据相关联。在一系列体外和体内模型和分子分析中，我们表征了这种 lncRNA 的基本生物学作用。我们进一步探索了在结直肠癌 (CRC) 转移的小鼠模型中靶向 FLANC 的治疗潜力。结果 FLANC 是一种在正常结肠细胞中微弱表达的灵长类特异性 lncRNA，与两个独立队列中的正常结肠样本相比，在癌细胞中显着上调。在另外两个独立的 CRC 患者队列中，高水平的 FLANC 与较差的存活率相关。体外和体内实验均表明，FLANC 表达的调节影响了 CRC 细胞的细胞生长、凋亡、迁移、血管生成和转移形成能力。通过施用载有特定小干扰 RNA 的 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine 纳米颗粒对 FLANC 进行体内药理学靶向，诱导转移显着减少，没有明显的组织毒性或促炎作用。从机制上讲，FLANC 上调并延长磷酸化 STAT3 的半衰期，诱导血管生成的关键调节因子 VEGFA 的过度表达。结论 根据我们的发现，我们发现，FLANC 作为一种新型灵长类特异性 lncRNA，在 CRC 细胞中高度上调并调节转移形成。靶向灵长类动物特异性转录物如 FLANC 可能代表一种用于治疗患者的新型低毒治疗策略。