Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, P. R. China.
CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China.
Cell Death Dis. 2023 Aug 9;14(8):511. doi: 10.1038/s41419-023-06034-1.
Dysregulation of serine/arginine splicing factors (SRSFs) and abnormal alternative splicing (AS) have been widely implicated in various cancers but scarcely investigated in nasopharyngeal carcinoma (NPC). Here we examine the expression of 12 classical SRSFs between 87 NPC and 10 control samples, revealing a significant upregulation of SRSF3 and its association with worse prognosis in NPC. Functional assays demonstrate that SRSF3 exerts an oncogenic function in NPC progression. Transcriptome analysis reveals 1,934 SRSF3-regulated AS events in genes related to cell cycle and mRNA metabolism. Among these events, we verify the generation of a long isoform of AMOTL1 (AMOTL1-L) through a direct bond of the SRSF3 RRM domain with the exon 12 of AMOTL1 to promote exon inclusion. Functional studies also reveal that AMOTL1-L promotes the proliferation and migration of NPC cells, while AMOTL1-S does not. Furthermore, overexpression of AMOTL1-L, but not -S, significantly rescues the inhibitory effects of SRSF3 knockdown. Additionally, compared with AMOTL1-S, AMOTL1-L has a localization preference in the intracellular than the cell membrane, leading to a more robust interaction with YAP1 to promote nucleus translocation. Our findings identify SRSF3/AMOTL1 as a novel alternative splicing axis with pivotal roles in NPC development, which could serve as promising prognostic biomarkers and therapeutic targets for NPC.
丝氨酸/精氨酸剪接因子（SRSFs）的失调和异常的选择性剪接（AS）已广泛涉及各种癌症，但在鼻咽癌（NPC）中研究甚少。在这里，我们检查了 87 个 NPC 和 10 个对照样本之间 12 种经典 SRSFs 的表达情况，发现 SRSF3 的显著上调与 NPC 的预后不良有关。功能测定表明 SRSF3 在 NPC 进展中具有致癌功能。转录组分析揭示了 1,934 个与细胞周期和 mRNA 代谢相关的基因中 SRSF3 调节的 AS 事件。在这些事件中，我们通过 SRSF3 RRM 结构域与 AMOTL1 外显子 12 的直接结合来验证 AMOTL1-L 的长亚型的产生，以促进外显子包含。功能研究还表明，AMOTL1-L 促进 NPC 细胞的增殖和迁移，而 AMOTL1-S 则没有。此外，AMOTL1-L 的过表达，而不是 -S，可显著挽救 SRSF3 敲低的抑制作用。此外，与 AMOTL1-S 相比，AMOTL1-L 在内质网中而不是细胞膜中的定位偏好，导致与 YAP1 更强烈的相互作用，促进核易位。我们的研究结果确定了 SRSF3/AMOTL1 作为 NPC 发展中具有关键作用的新型选择性剪接轴，它可以作为 NPC 的有前途的预后生物标志物和治疗靶点。
