School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei Province, People's Republic of China.
Department of Gastroenterology, Affiliated Hospital of North China University of Technology, Tangshan, 063007, Hebei Province, People's Republic of China.
BMC Med Genomics. 2022 Aug 15;15(1):180. doi: 10.1186/s12920-022-01316-7.
Serine and arginine-rich splicing factor 9 (SRSF9) has been linked to the occurrence and progression of various cancers; however, its effects and mechanism of action hepatocellular carcinoma (HCC) have not been reported. In this study, we used a bioinformatics approach and in vitro assays to evaluate the expression of SRSF9 in HCC, its prognostic value, and its underlying regulatory mechanisms, including analyses of related pathways and the role of methylation.
Transcriptomic and DNA methylation data for 357 HCC cases and 50 paratumor tissues in The Cancer Genome Atlas database were obtained. Additionally, protein expression data for cell lines and tissue samples were obtained from the Human Protein Atlas. The CMap databased was used to predict candidate drugs targeting SRSF9. Various cell lines were used for in vitro validation.
SRSF9 expression was significantly elevated in HCC and was negatively regulated by its methylation site cg06116271. The low expression of SRSF9 and hypermethylation of cg06116271 were both associated with a longer overall survival time. A correlation analysis revealed ten genes that were co-expressed with SRSF9; levels of CDK4, RAN, DENR, RNF34, and ANAPC5 were positively correlated and levels of RBP4, APOC1, MASP2, HP, and HPX were negatively correlated with SRSF9 expression. The knockdown of SRSF9 in vitro inhibited the proliferation and migration of HCC cells and significantly reduced the expression of proteins in the Wnt signaling pathway (DVL2 and β-catenin) and cell cycle pathway (Cyclin D and Cyclin E). A CMap analysis identified two drugs, camptothecin and apigenin, able to target and inhibit the expression of SRSF9.
This study expands our understanding of the molecular biological functions of SRSF9 and cg06116271 and provides candidate diagnostic and therapeutic targets for HCC.
丝氨酸/精氨酸丰富剪接因子 9（SRSF9）与多种癌症的发生和进展有关；然而，其在肝细胞癌（HCC）中的作用和机制尚未报道。在这项研究中，我们使用生物信息学方法和体外实验来评估 SRSF9 在 HCC 中的表达、其预后价值以及潜在的调控机制，包括相关通路分析和甲基化作用。
从癌症基因组图谱（TCGA）数据库中获取 357 例 HCC 病例和 50 例癌旁组织的转录组和 DNA 甲基化数据。此外，从人类蛋白质图谱中获取细胞系和组织样本的蛋白表达数据。使用 CMap 数据库预测针对 SRSF9 的候选药物。使用各种细胞系进行体外验证。
SRSF9 在 HCC 中表达显著上调，且受其甲基化位点 cg06116271 的负调控。SRSF9 低表达和 cg06116271 高甲基化均与总生存期延长相关。相关性分析显示与 SRSF9 共表达的十个基因；CDK4、RAN、DENR、RNF34 和 ANAPC5 的水平呈正相关，而 RBP4、APOC1、MASP2、HP 和 HPX 的水平与 SRSF9 表达呈负相关。体外敲低 SRSF9 抑制 HCC 细胞的增殖和迁移，并显著降低 Wnt 信号通路（DVL2 和 β-catenin）和细胞周期通路（Cyclin D 和 Cyclin E）中的蛋白表达。CMap 分析鉴定出两种能够靶向并抑制 SRSF9 表达的药物，喜树碱和芹菜素。
本研究扩展了我们对 SRSF9 和 cg06116271 的分子生物学功能的理解，并为 HCC 提供了候选诊断和治疗靶点。
