Chang Yu-Ching, Wu Chung-Ze, Cheng Chao-Wen, Chen Jin-Shuen, Chang Li-Chien
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City 114201, Taiwan.
Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110301, Taiwan.
Pharmaceuticals (Basel). 2023 Oct 9;16(10):1435. doi: 10.3390/ph16101435.
During tumorigenesis, urokinase (uPA) and uPA receptor (uPAR) play essential roles in mediating pathological progression in many cancers. To understand the crosstalk between the uPA/uPAR signaling and cancer, as well as to decipher their cellular pathways, we proposed to use cancer driver genes to map out the uPAR signaling. In the study, an integrated pharmaceutical bioinformatics approach that combined modulator identification, driver gene ontology networking, protein targets prediction and networking, pathway analysis and uPAR modulator screening platform construction was employed to uncover druggable targets in uPAR signaling for developing a novel anti-cancer modality. Through these works, we found that uPAR signaling interacted with 10 of 21 KEGG cancer pathways, indicating the important role of uPAR in mediating intracellular cancerous signaling. Furthermore, we verified that receptor tyrosine kinases (RTKs) and ribosomal S6 kinases (RSKs) could serve as signal hubs to relay uPAR-mediated cellular functions on cancer hallmarks such as angiogenesis, proliferation, migration and metastasis. Moreover, we established an in silico virtual screening platform and a uPAR-driver gene pair rule for identifying potential uPAR modulators to combat cancer. Altogether, our results not only elucidated the complex networking between uPAR modulation and cancer but also provided a paved way for developing new chemical entities and/or re-positioning clinically used drugs against cancer.
在肿瘤发生过程中，尿激酶（uPA）和尿激酶受体（uPAR）在介导多种癌症的病理进展中发挥着重要作用。为了了解uPA/uPAR信号与癌症之间的相互作用，并破译它们的细胞途径，我们提议使用癌症驱动基因来绘制uPAR信号图谱。在这项研究中，采用了一种综合的药物生物信息学方法，该方法结合了调节剂鉴定、驱动基因本体网络、蛋白质靶点预测与网络构建、通路分析以及uPAR调节剂筛选平台构建，以揭示uPAR信号中可成药的靶点，从而开发一种新型抗癌模式。通过这些工作，我们发现uPAR信号与21条KEGG癌症通路中的10条相互作用，这表明uPAR在介导细胞内癌症信号传导中起着重要作用。此外，我们证实受体酪氨酸激酶（RTKs）和核糖体S6激酶（RSKs）可作为信号枢纽，在血管生成、增殖、迁移和转移等癌症特征方面传递uPAR介导的细胞功能。此外，我们建立了一个计算机虚拟筛选平台和一个uPAR-驱动基因对规则，用于识别潜在的抗癌uPAR调节剂。总之，我们的结果不仅阐明了uPAR调节与癌症之间的复杂网络，还为开发新的化学实体和/或重新定位临床使用的抗癌药物铺平了道路。
