Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Mol Cancer. 2020 Jul 15;19(1):115. doi: 10.1186/s12943-020-01232-3.
Long non-coding RNAs (lncRNAs) have been identified as important epigenetic regulators that play critical roles in human cancers. However, the regulatory functions of lncRNAs in tumorigenesis remains to be elucidated. Here, we aimed to investigate the molecular mechanisms and potential clinical application of a novel lncRNA, retinoblastoma associated transcript-1 (RBAT1), in tumorigenesis.
RBAT1 expression was determined by real-time PCR in both retinoblastoma (Rb) and bladder cancer (BCa) cell lines and clinical tissues. Chromatin isolation using RNA purification (ChIRP) assays were performed to identify RBAT1-interacting proteins. Patient-derived xenograft (PDX) retinoblastoma models were established to test the therapeutic potential of RBAT1-targeting GapmeRs.
Here, we found that RBAT1 expression was significantly higher in Rb and BCa tissues than that in adjacent tissues. Functional assays revealed that RBAT1 accelerated tumorigenesis both in vitro and in vivo. Mechanistically, RBAT1 recruited HNRNPL protein to E2F3 promoter, thereby activating E2F3 transcription. Therapeutically, GapmeR-mediated RBAT1 silencing significantly inhibited tumorigenesis in orthotopic xenograft retinoblastoma models derived from Rb cell lines and Rb primary cells.
RBAT1 overexpression upregulates a known oncogene, E2F3, via directly recruiting HNPNPL to its promoter and cis-activating its expression. Our finding provides a novel mechanism of lncRNA biology and provides potential targets for diagnosis and treatment of Rb and BCa.
长链非编码 RNA（lncRNA）已被鉴定为重要的表观遗传调控因子，在人类癌症中发挥关键作用。然而，lncRNA 在肿瘤发生中的调控功能仍有待阐明。在这里，我们旨在研究新型 lncRNA 视网膜母细胞瘤相关转录物-1（RBAT1）在肿瘤发生中的分子机制和潜在临床应用。
通过实时 PCR 检测 RBAT1 在视网膜母细胞瘤（Rb）和膀胱癌（BCa）细胞系和临床组织中的表达。采用 RNA 纯化（ChIRP）实验进行染色质分离，以鉴定 RBAT1 相互作用蛋白。建立患者来源的异种移植（PDX）视网膜母细胞瘤模型，以测试 RBAT1 靶向 GapmeRs 的治疗潜力。
我们发现 RBAT1 在 Rb 和 BCa 组织中的表达明显高于相邻组织。功能测定表明，RBAT1 在体外和体内均加速了肿瘤的发生。在机制上，RBAT1 募集 HNRNPL 蛋白到 E2F3 启动子，从而激活 E2F3 转录。治疗上，GapmeR 介导的 RBAT1 沉默显著抑制了源自 Rb 细胞系和 Rb 原代细胞的原位异种移植视网膜母细胞瘤模型中的肿瘤发生。
RBAT1 的过表达通过直接招募 HNRNPL 到其启动子并顺式激活其表达，上调了一个已知的癌基因 E2F3。我们的发现为 lncRNA 生物学提供了一个新的机制，并为 Rb 和 BCa 的诊断和治疗提供了潜在的靶点。
