Huang Kexin, Zhang Yun, Shi Xiaorui, Yin Zhiqin, Zhao Weiling, Huang Liyu, Wang Fu, Zhou Xiaobo
School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China.
West China Biomedical Big Data Centre, West China Hospital of Sichuan University, Chengdu 610041, China.
Mol Ther Nucleic Acids. 2023 Aug 11;33:816-831. doi: 10.1016/j.omtn.2023.08.005. eCollection 2023 Sep 12.
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.
异常的可变聚腺苷酸化（APA）常通过调控癌基因和肿瘤抑制基因的表达参与肿瘤发生和癌症进展。然而，对肿瘤类型和细胞类型特异性APA事件的了解有限可能导致新的APA事件及其功能被忽视。在此，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，并在NSCLC中鉴定了功能相关的APA事件。我们发现了几种调节基因表达变化的细胞特异性3'-UTR改变，这些改变在NSCLC中具有预后价值。我们进一步研究了通过丢失微小RNA（miRNA）结合位点介导的APA导致3'-UTR缩短的功能，并鉴定并通过实验验证了几条癌基因-miRNA-肿瘤抑制轴。根据我们的分析，我们发现SPARC是NSCLC中癌症相关成纤维细胞中受APA调控的癌基因。敲低SPARC可减弱肺癌细胞的侵袭和转移。此外，我们发现高SPARC表达与除顺铂外的几种药物耐药相关。与低SPARC表达的患者相比，高SPARC表达的NSCLC患者接受顺铂治疗可能获益更多。总体而言，我们对细胞特异性APA事件的综合分析揭示了细胞特异性癌基因的调控机制，并为将APA调控的治疗靶点与细胞特异性治疗开发相结合提供了机会。
