Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here, we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDACs). We report widespread, recurrent, and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDAC growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDAC pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.

中文翻译：

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替代多聚腺苷酸化驱动胰腺导管腺癌中的致癌基因表达。

替代多聚腺苷酸化 (APA) 是一种基因调控过程，决定 mRNA 3'-UTR 长度，导致 mRNA 稳定性和定位发生变化。APA 在癌症中经常被破坏，并通过改变癌基因和肿瘤抑制因子的表达来促进肿瘤发生。泛癌分析揭示了肿瘤领域常见的 APA 事件；然而，人们对可能发现新事件和脆弱性的肿瘤类型特异性改变知之甚少。在这里，我们整合了来自基因型组织表达 (GTEx) 项目和癌症基因组图谱 (TCGA) 的 RNA 测序数据，以全面分析 148 例胰腺导管腺癌 (PDAC) 中的 APA 事件。我们报告了与已知和新发现的 PDAC 生长促进基因的基因表达变化相关的广泛、重复和功能相关的 3'-UTR 改变，并通过实验验证了这些 APA 事件对蛋白质表达的影响。我们发现与已知 PDAC 通路相关的基因中 APA 事件富集、肿瘤抑制 miRNA 结合位点的丢失以及代谢基因 3'-UTR 形式的异质性增加。生存分析揭示了 3'-UTR 改变的一个子集，这些改变独立地表征了 PDAC 患者中预后不良的队列。最后，我们确定并验证了酪蛋白激酶 CSNK1A1（也称为 CK1α 或 CK1a）作为 PDAC 中 APA 调节的治疗靶点。CSNK1A1 的敲低或药物抑制会减弱 PDAC 细胞增殖和克隆生长。我们的单一癌症分析表明，APA 通过失去 miRNA 调节而成为 PDAC 中促肿瘤基因表达的一个未被充分认识的驱动因素。