KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1 |
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| Authors: | Qing Hua Zhirong Sun Yi Liu Xuefang Shen Weiwei Zhao Xiaoyan Zhu Pingbo Xu |
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| Affiliation: | 1.Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China ;2.Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong an Road, 200032 Shanghai, China ;3.Department of Anesthesiology, Zhongshan Hospital, Fudan University, 200032 Shanghai, China ;4.Department of Integrated Therapy, Fudan University Shanghai Cancer Centre, Shanghai, China ;5.Department of Physiology, Navy Medical University, 800 Xiangyin Road, 200433 Shanghai, China |
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| Abstract: | 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 {"type":"entrez-protein","attrs":{"text":"SCH79797","term_id":"1052762130","term_text":"SCH79797"}}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 {"type":"entrez-protein","attrs":{"text":"SCH79797","term_id":"1052762130","term_text":"SCH79797"}}SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, {"type":"entrez-protein","attrs":{"text":"SCH79797","term_id":"1052762130","term_text":"SCH79797"}}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.Subject terms: Colorectal cancer, Oncogenes, Tumour biomarkers |
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