Cheng Shanshan, Ray Debleena, Lee Raymond Teck Ho, Naripogu Kishore Babu, Yusoff Permeen Akhtar Bt Mohamed, Goh Pamela Bee Leng, Liu Yujing, Suzuki Yuka, Das Kakoli, Chan Hsiang Sui, Wong Wai Keong, Chan Weng Hoong, Chow Pierce Kah-Hoe, Ong Hock Soo, Raj Prema, Soo Khee Chee, Tan Patrick, Epstein David M, Rozen Steven G
Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, Hubei 430030, China.
Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.
NAR Genom Bioinform. 2020 Feb 28;2(2):lqaa013. doi: 10.1093/nargab/lqaa013. eCollection 2020 Jun.
Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor-normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (, and ). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.
目前对胃癌中异常剪接的全面了解尚缺。我们对19对胃肿瘤-正常组织进行了RNA测序，基于高覆盖度测序和严格筛选，鉴定出118个高可信度的肿瘤相关（TA）可变剪接事件（ASE），同时还鉴定出8个差异表达的剪接因子（SF）。TA ASE发生在主要参与细胞骨架组织的基因中。我们构建了TA ASE剪接比率与SF表达之间的关联网络，并在来自癌症基因组图谱的独立胃癌数据中进行了复制，并通过敲低关键SF（ 、 和 ）进行了实验验证。每个SF的敲低都导致了几个相应TA ASE的剪接改变，并导致细胞迁移改变，这与TA ASE在细胞骨架组织中的作用一致。因此，我们建立了一个与胃癌肿瘤侵袭相关的失调剪接的稳健网络。我们的工作为鉴定致癌剪接形式、SF和剪接产生的肿瘤抗原作为生物标志物和治疗靶点提供了资源。
