Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Urology, Nantong Tongzhou People's Hospital, Nantong 226000, China.
Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
Cell Signal. 2021 May;81:109932. doi: 10.1016/j.cellsig.2021.109932. Epub 2021 Jan 29.
The pathogenesis of bladder cancer (BLCa) is still unclear. Long non-coding RNAs (lncRNAs) participate in diverse biological processes across every branch of life, especially in cancer. Dysregulated lncRNAs in BLCa and their biological significance require further investigations.
Herein, a differential expression profile of lncRNAs in BLCa was conducted by microarray data. The expression level of lncRNA LINC01451 in 70 pairs of BLCa tissue samples and different BLCa cell lines were analyzed via real-time quantitative PCR. The CRISPR-CAS9 technique was employed to establish the LINC01451 stably transfected cell lines. Loss-of-function, as well as gain-of-function assays were carried out to evaluate the effects of LINC01451 on cell proliferation, migration, and invasion. Patient-derived xenograft (PDX) mouse models were adopted in the in vivo experiments. Western blot, biotinylated RNA probe pull-down assay, fluorescence in situ hybridization, and immunohistochemistry were utilized to assess the underlying molecular mechanisms of LINC01451 in BLCa.
LINC01451 was identified a novel functional lncRNA, whose expression level in BLCa tissues was significantly higher compared with the normal tissues. Furthermore, it was found that LINC01451 directly docked LIN28A and LIN28B, and promoted the proliferation, invasion, and metastasis of BLCa. Mechanistically, LINC0145 was shown to depend on LIN28A and LIN28B, facilitated epithelial-mesenchymal transition (EMT) through activating the TGF-β/Smad signaling pathway, which subsequently aggravated BLCa progression.
We demonstrates that LINC01451 drives EMT-induced BLCa progression by activating the LIN28/TGF-β/Smad signaling pathway. Promisingly, LINC01451 acts as a prognostic biomarker and a novel therapeutic target for BLCa.
膀胱癌（BLCa）的发病机制尚不清楚。长链非编码 RNA（lncRNA）参与了生命各个分支的多种生物学过程，尤其是在癌症中。BLCa 中失调的 lncRNA 及其生物学意义需要进一步研究。
本研究通过微阵列数据分析了 BLCa 中 lncRNA 的差异表达谱。通过实时定量 PCR 分析了 70 对 BLCa 组织样本和不同 BLCa 细胞系中 lncRNA LINC01451 的表达水平。采用 CRISPR-CAS9 技术构建 LINC01451 稳定转染细胞系。进行了失能和获得功能实验，以评估 LINC01451 对细胞增殖、迁移和侵袭的影响。在体内实验中采用了患者来源的异种移植（PDX）小鼠模型。采用 Western blot、生物素化 RNA 探针下拉实验、荧光原位杂交和免疫组织化学方法评估了 LINC01451 在 BLCa 中的潜在分子机制。
鉴定出 LINC01451 是一种新型功能性 lncRNA，其在 BLCa 组织中的表达水平明显高于正常组织。此外，发现 LINC01451 可直接与 LIN28A 和 LIN28B 结合，并促进 BLCa 的增殖、侵袭和转移。机制上，LINC01451 依赖于 LIN28A 和 LIN28B，通过激活 TGF-β/Smad 信号通路促进上皮间质转化（EMT），进而加重 BLCa 进展。
本研究证明 LINC01451 通过激活 LIN28/TGF-β/Smad 信号通路驱动 EMT 诱导的 BLCa 进展。有希望的是，LINC01451 可作为 BLCa 的预后生物标志物和新型治疗靶点。
