Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
Neoplasia. 2024 Jan;47:100963. doi: 10.1016/j.neo.2023.100963. Epub 2024 Jan 3.
Muscle-invasive and metastatic bladder cancer indicates extra worse prognosis. Accumulating evidence roots for the prominent role of circular RNAs(circRNAs) in bladder cancer, while the mechanisms linking circRNAs and bladder cancer metastasis remain limitedly investigated. Here, we identified a significantly upregulated circRNA candidate, hsa_circ_0001583, from online datasets. Validated by qRT-PCR, PCR, sanger sequencing, actinomycin D and RNase R digestion experiments, hsa_circ_0001583 was proved to be a genuine circular RNA with higher expression levels in bladder cancer tissue. Through gain and loss of function experiments, hsa_circ_0001583 exhibited potent migration and invasion powers both in vitro and in vivo. The staphylococcal nuclease and Tudor domain containing 1 (SND1) was identified as an authentic binding partner for hsa_circ_0001583 through RNA pulldown and RIP experiments. Elevated levels of hsa_circ_0001583 could bind more to SND1 and protect the latter from degradation. Rescue experiments demonstrated that such interaction-induced increased in SND1 levels in bladder cancer cells enabled the protein to pump its endonuclease activity, leading to the degradation of tumor-suppressing MicroRNAs (miRNAs) including miR-126-3p, the suppressor of Disintegrin And Metalloproteinase Domain-Containing Protein 9 (ADAM9), ultimately driving cells into a highly migrative and invasive state. In summary, our study is the first to highlight the upregulation of hsa_circ_0001583 in bladder cancer and its role in downregulating miR-126-3p by binding to and stabilizing the SND1 protein, thereby promoting bladder cancer cell migration and invasion. This study adds hsa_circ_0001583 to the pool of bladder cancer metastasis biomarkers and therapeutic targets.
肌层浸润性和转移性膀胱癌表示预后更差。越来越多的证据表明环状 RNA（circRNAs）在膀胱癌中具有重要作用，而将 circRNAs 与膀胱癌转移相关的机制仍研究有限。在这里，我们从在线数据库中鉴定出一个显著上调的环状 RNA 候选物 hsa_circ_0001583。通过 qRT-PCR、PCR、Sanger 测序、放线菌素 D 和 RNase R 消化实验验证，hsa_circ_0001583 被证明是一种真正的环状 RNA，在膀胱癌组织中表达水平更高。通过 gain 和 loss of function 实验，hsa_circ_0001583 在体外和体内均表现出强大的迁移和侵袭能力。通过 RNA 下拉和 RIP 实验，鉴定出葡萄球菌核酸酶和 Tudor 结构域包含蛋白 1（SND1）是 hsa_circ_0001583 的真实结合伴侣。通过 RNA 下拉和 RIP 实验，鉴定出葡萄球菌核酸酶和 Tudor 结构域包含蛋白 1（SND1）是 hsa_circ_0001583 的真实结合伴侣。通过 RNA 下拉和 RIP 实验，鉴定出葡萄球菌核酸酶和 Tudor 结构域包含蛋白 1（SND1）是 hsa_circ_0001583 的真实结合伴侣。升高的 hsa_circ_0001583 水平可以与更多的 SND1 结合，并保护后者免受降解。挽救实验表明，这种相互作用诱导的膀胱癌细胞中 SND1 水平的增加使该蛋白能够泵出其内切酶活性，导致肿瘤抑制 microRNA（miRNA）包括 miR-126-3p 的降解，Disintegrin And Metalloproteinase Domain-Containing Protein 9（ADAM9）的抑制剂，最终将细胞推向高度迁移和侵袭状态。总之，我们的研究首次强调了 hsa_circ_0001583 在膀胱癌中的上调及其通过与 SND1 蛋白结合并稳定该蛋白来下调 miR-126-3p 的作用，从而促进膀胱癌细胞的迁移和侵袭。这项研究将 hsa_circ_0001583 添加到膀胱癌转移生物标志物和治疗靶点的库中。
