Department of Head and Neck Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University & The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center Nanjing, Nanjing Medical University, Nanjing, China; Wuxi People's Hospital, Wuxi Medical Center Nanjing & Department of Immunology, School of Basic Medical Science & Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China.
Nanjing Red Cross Blood Center, Nanjing, China.
Cancer Lett. 2024 Nov 1;604:217270. doi: 10.1016/j.canlet.2024.217270. Epub 2024 Sep 19.
Alternative splicing (AS) plays a crucial role in the hallmarks of cancer and can open new avenues for targeted therapies. However, the aberrant AS events and the metastatic cascade in papillary thyroid carcinoma (PTC) remain largely unclear. Here, we identify the splicing factor, quaking protein (QKI), which was significantly downregulated in PTC and correlated with poor survival outcomes in patients with PTC. Functional studies indicated that low expression of QKI promoted the PTC cell growth and metastasis in vitro and in vivo. Mechanistically, low QKI induced exon 14 retention of extended synaptotagmin 2 (E-Syt2) and produced a long isoform transcript (termed E-Syt2L) that acted as an important oncogenic factor of PTC metastasis. Notably, overexpression of long non-coding RNA eosinophil granule ontogeny transcript (EGOT) physically binds to QKI and suppressed its activity by inhibiting ubiquitin specific peptidase 25 (USP25) mediated deubiquitination and subsequent degradation of QKI. Collectively, these data demonstrate the novel mechanistic links between the splicing factor QKI and splicing event in PTC metastasis and support the potential utility of targeting splicing events as a therapeutic strategy for PTC.
可变剪接（AS）在癌症的标志性特征中起着至关重要的作用，并为靶向治疗开辟了新的途径。然而，甲状腺乳头状癌（PTC）中的异常 AS 事件和转移级联仍然很大程度上不清楚。在这里，我们鉴定了剪接因子 QKI，其在 PTC 中显著下调，并与 PTC 患者的不良生存结局相关。功能研究表明，QKI 的低表达促进了 PTC 细胞在体外和体内的生长和转移。在机制上，低 QKI 诱导延伸突触结合蛋白 2（E-Syt2）的外显子 14 保留，并产生一种长的异构体转录本（称为 E-Syt2L），作为 PTC 转移的重要致癌因子。值得注意的是，长非编码 RNA 嗜酸性粒细胞发生转录物（EGOT）的过表达与 QKI 物理结合，并通过抑制泛素特异性肽酶 25（USP25）介导的去泛素化和随后的 QKI 降解来抑制其活性。总的来说，这些数据表明了 PTC 转移中剪接因子 QKI 和剪接事件之间的新的机制联系，并支持将剪接事件作为 PTC 的治疗策略的潜在效用。
