PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.
摘要：
胰腺导管腺癌（PDAC）在预后和治疗方面提出了重大挑战。最近的研究已经确定剪接失调是一种新的癌症标志。在这里，我们调查了PDAC胰腺细胞和组织中大部分未表征的选择性剪接谱和关键剪接因子SF3B1,将其作为可能的药物靶点和新的临床结局预测生物标志物的潜在发现来源.这项研究涉及全转录组分析，比较PDAC原代细胞与正常导管细胞的剪接谱。这揭示了参与基因表达调控的基因中超过400个显著的差异剪接事件,主要与mRNA剪接有关，和核酸的代谢。PDAC培养物对SF3B1调节剂高度敏感，E7107和帕地烯醇内酯-B，显示IC50在低纳摩尔范围内。这些化合物诱导细胞凋亡，与MCL-1/S剪接变体的诱导相关。减少细胞迁移，与RON错误拼接有关。在原位小鼠模型中，E7107显示出有希望的结果。此外，我们评估了87例患者的SF3B1表达,发现SF3B1表达与无进展生存期和总生存期显著相关.总之,SF3B1在PDAC中既是潜在的预后因素，也是治疗靶点，影响细胞增殖，迁移,和凋亡。这些发现保证了对这种针对PDAC的新治疗策略的未来研究。
