New Drug Screening Center, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, China.
Guangzhou Customs District Technology Center, Guangzhou, China.
Br J Cancer. 2024 Jul;131(1):77-89. doi: 10.1038/s41416-024-02689-5. Epub 2024 May 25.
Due to insufficient knowledge about key molecular events, Hepatocellular carcinoma (HCC) lacks effective treatment targets. Spliceosome-related genes were significantly altered in HCC. Oncofetal proteins are ideal tumor therapeutic targets. Screening of differentially expressed Spliceosome-related oncofetal protein in embryonic liver development and HCC helps discover effective therapeutic targets for HCC.
Differentially expressed spliceosome genes were analysis in fetal liver and HCC through bioinformatics analysis. Small nuclear ribonucleoprotein polypeptide E (SNRPE) expression was detected in fetal liver, adult liver and HCC tissues. The role of SNRPE in HCC was performed multiple assays in vitro and in vivo. SNRPE-regulated alternative splicing was recognized by RNA-Seq and confirmed by multiple assays.
We herein identified SNRPE as a crucial oncofetal splicing factor, significantly associated with the adverse prognosis of HCC. SOX2 was identified as the activator for SNRPE reactivation. Efficient knockdown of SNRPE resulted in the complete cessation of HCC tumorigenesis and progression. Mechanistically, SNRPE knockdown reduced FGFR4 mRNA expression by triggering nonsense-mediated RNA decay. A partial inhibition of SNRPE-induced malignant progression of HCC cells was observed upon FGFR4 knockdown.
Our findings highlight SNRPE as a novel oncofetal splicing factor and shed light on the intricate relationship between oncofetal splicing factors, splicing events, and carcinogenesis. Consequently, SNRPE emerges as a potential therapeutic target for HCC treatment. Model of oncofetal SNRPE promotes HCC tumorigenesis by regulating the AS of FGFR4 pre-mRNA.
由于对关键分子事件的了解不足，肝细胞癌 (HCC) 缺乏有效的治疗靶点。剪接体相关基因在 HCC 中发生明显改变。癌胚蛋白是理想的肿瘤治疗靶点。筛选胚胎肝发育和 HCC 中差异表达的剪接体相关癌胚蛋白有助于发现 HCC 的有效治疗靶点。
通过生物信息学分析分析胎儿肝和 HCC 中差异表达的剪接体基因。检测小核核糖核蛋白多肽 E (SNRPE) 在胎儿肝、成人肝和 HCC 组织中的表达。在体外和体内进行多种试验研究 SNRPE 在 HCC 中的作用。通过 RNA-Seq 识别 SNRPE 调节的可变剪接，并通过多种试验进行验证。
我们在此鉴定 SNRPE 为关键的癌胚剪接因子，与 HCC 的不良预后显著相关。SOX2 被鉴定为 SNRPE 重新激活的激活剂。SNRPE 的有效敲低导致 HCC 肿瘤发生和进展完全停止。机制上，SNRPE 敲低通过触发无意义介导的 RNA 降解降低 FGFR4 mRNA 表达。FGFR4 敲低观察到 SNRPE 诱导的 HCC 细胞恶性进展部分抑制。
我们的研究结果强调了 SNRPE 作为一种新型癌胚剪接因子的作用，并揭示了癌胚剪接因子、剪接事件和致癌之间的复杂关系。因此，SNRPE 成为 HCC 治疗的潜在治疗靶点。癌胚 SNRPE 模型通过调节 FGFR4 前体 mRNA 的 AS 促进 HCC 肿瘤发生。
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