Li Junyi, Pan Tao, Chen Liuxin, Wang Qi, Chang Zhenghong, Zhou Weiwei, Li Xinhui, Xu Gang, Li Xia, Li Yongsheng, Zhang Yunpeng
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China.
Mol Ther Nucleic Acids. 2021 Apr 9;24:792-806. doi: 10.1016/j.omtn.2021.04.005. eCollection 2021 Jun 4.
Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.
可变剪接（AS）在基因调控中发挥着重要作用，并且在癌症中经常观察到AS的扰动。RNA结合蛋白（RBP）是AS的分子决定因素之一，RBP-基因网络活性的扰动与癌症发展存在因果关系。在此，我们进行了一项系统分析，以表征18种癌症类型中AS事件的扰动情况。我们发现AS改变在癌症中普遍存在，并涉及与癌症相关的通路。鉴于AS扰动的程度与疾病严重程度相关，我们提出了一种计算流程来鉴定RBP调节因子。泛癌分析鉴定出了许多保守的RBP调节因子，它们在调节参与癌症特征性通路的基因的AS中发挥重要作用。我们的应用分析表明，68种RBP调节因子的表达有助于癌症亚型分类。具体而言，我们鉴定出了肾癌的四种亚型，它们在癌症特征性通路活性和预后方面存在差异。最后，我们鉴定出了可能靶向RBP基因的小分子，并提出了癌症治疗的潜在候选药物。总之，我们全面的AS扰动图谱分析确定了RBP作为癌症潜在的治疗靶点，并为RBP在癌症中的调控功能提供了新的见解。
