Kallikrein-Related Peptidase 4 Promotes Proliferation, Migration, Invasion, and Pro-Angiogenesis of Endometrial Stromal Cells via Regulation of Brain-Derived Neurotrophic Factor Production in Endometriosis

Endometriosis is a common benign gynecologic condition. Endometriosis lesions are associated with endometrial cell proliferation, migration, invasion, and neovascularization, while the specific molecular mechanisms are still elusive. Transcriptome sequencing has been used for the identification of diagnostic markers in endometriosis. Here, transcriptome profiling revealed that kallikrein related peptidase 4 (KLK4) expression was up-regulated in ectopic endometrium (EC) tissues of patients with endometriosis. KLK4 mediates the degradation of extracellular matrix proteins, and its proteolytic activity activates many tumorigenic and metastatic pathways via tumor invasion and migration. Nevertheless, whether KLK4 serves as an important regulatory factor in endometriosis remains unclear. We confirmed that KLK4 was highly expressed in ectopic endometrial stromal cells (ESCs). Next, we revealed that KLK4 overexpression promoted proliferation and, suppressed apoptosis of EC-ESCs, and induced cell migration and invasion, as well as enhanced angiogenesis in vivo. Mechanistically, KLK4 overexpression mediated the protein cleavage of pro-BDNF in EC-ESCs. Finally, we showed that BDNF as a vital downstream substrate of KLK4 maintained the proliferation, metastasis, and pro-angiogenesis abilities and inhibited apoptosis of ESCs through a rescue study. Together, our findings demonstrate the promotive role of KLK4 in endometriosis development. In addition, our study provides a new insight that KLK4 might be a potential therapeutic target and prognostic marker for endometriosis patients.