Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong an Road, 200032, Shanghai, China.
Cell Death Dis. 2021 Sep 22;12(10):860. doi: 10.1038/s41419-021-04149-x.
Kallikrein-related peptidase 8 (KLK8) acts as an oncogene or anti-oncogene in various tumours, and the abnormal expression of KLK8 is involved in the carcinogenesis of several tumours. However, the role of KLK8 in colorectal cancer (CRC) and the underlying mechanism remain largely unclear. In this study, the carcinogenic effect of KLK8 was determined via CCK-8 and colony formation assays in vitro and a xenograft model in nude mice in vivo. The metastasis-promoting effect of KLK8 was investigated with transwell migration and invasion assays and wound-healing assay in vitro and a metastasis model in nude mice in vivo. Bioinformatics analyses and mechanistic experiments were conducted to elucidate the molecular mechanism. Herein, we reported that KLK8 had a promotive effect on the proliferation, migration and invasion of RKO and SW480 cells. Epithelial-mesenchymal transition (EMT) played an important role in the promotive effects of KLK8 on CRC. In addition, protease-activated receptor-1 (PAR-1) antagonist SCH79797 but not protease-activated receptor-2 (PAR-2) antagonist FSLLRY-NH2 attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells. PAR-1 antagonist SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, SCH79797 could reverse the positive impact of KLK8 on the EMT process in CRC both in vitro and in vivo. Taken together, these findings demonstrated for the first time that KLK8 promoted EMT and CRC progression, and this effect might be, at least partly mediated by PAR1-dependent pathway.
激肽释放酶相关肽酶 8（KLK8）在各种肿瘤中作为癌基因或抑癌基因发挥作用，KLK8 的异常表达参与了几种肿瘤的癌变过程。然而，KLK8 在结直肠癌（CRC）中的作用及其潜在机制在很大程度上仍不清楚。在本研究中，通过 CCK-8 和集落形成实验在体外和裸鼠异种移植模型中，以及 Transwell 迁移和侵袭实验、划痕愈合实验在体外和裸鼠转移模型中体内研究了 KLK8 的致癌作用。通过生物信息学分析和机制实验阐明了分子机制。在此，我们报道 KLK8 可促进 RKO 和 SW480 细胞的增殖、迁移和侵袭。上皮间质转化（EMT）在 KLK8 促进 CRC 中的作用中起着重要作用。此外，蛋白酶激活受体-1（PAR-1）拮抗剂 SCH79797 而不是蛋白酶激活受体-2（PAR-2）拮抗剂 FSLLRY-NH2 可减弱 KLK8 上调的 RKO 和 SW480 细胞的增殖、迁移和侵袭。PAR-1 拮抗剂 SCH79797 可减小异种移植模型中的肿瘤体积并减少转移模型中肝脏中的转移结节。此外，SCH79797 可在体外和体内逆转 KLK8 对 CRC 中 EMT 过程的正向影响。总之，这些发现首次表明 KLK8 促进 EMT 和 CRC 进展，这种作用至少部分是由 PAR1 依赖性途径介导的。
