破坏的选择性聚腺苷化（APA）通过调控癌基因和肿瘤抑制基因的基因表达，在肿瘤生成和癌症进展中经常发挥作用。然而，对于特定于肿瘤类型和细胞类型的APA事件的知识有限，可能会导致对新型APA事件及其功能的忽视。在这里，我们比较了非小细胞肺癌（NSCLC）和正常组织中不同细胞类型的APA事件，并确定了在NSCLC中与功能相关的APA事件。我们发现几个细胞特异性的3'-UTR改变能够调控基因表达变化，并在NSCLC中显示了预后价值。我们进一步通过miRNA结合位点的丧失来研究APA介导的3'-UTR缩短的功能，并鉴定并实验证实了几个癌基因-miRNA-肿瘤抑制基因轴。根据我们的分析，我们发现SPARC作为NSCLC中癌相关成纤维细胞中受APA调控的癌基因。敲除SPARC会减弱肺癌细胞的侵袭和转移能力。此外，我们发现高表达SPARC与除顺铂外的几种药物的耐药性相关。相比于顺铂低表达的患者，高表达SPARC的NSCLC患者可以获得更多的顺铂治疗效果。总的来说，我们对细胞特异性APA事件的全面分析揭示了细胞特异性癌基因的调控机制，并为APA调控的治疗靶标和细胞特异性治疗的发展提供了机会。© 2023 作者们。

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and we identified and experimentally validated several oncogene-miRNA-tumor suppressor axes. According to our analyses, we found SPARC as an APA-regulated oncogene in cancer-associated fibroblasts in NSCLC. Knockdown of SPARC attenuates lung cancer cell invasion and metastasis. Moreover, we found high SPARC expression associated with resistance to several drugs except cisplatin. NSCLC patients with high SPARC expression could benefit more compared to low-SPARC-expression patients with cisplatin treatment. Overall, our comprehensive analysis of cell-specific APA events shed light on the regulatory mechanism of cell-specific oncogenes and provided opportunities for combination of APA-regulated therapeutic target and cell-specific therapy development.© 2023 The Authors.