Kisspeptin 10 Inhibited the Proliferation, Migration, and Stemness of Esophageal Cancer Cells via Regulating the SIX1/Wnt/β-Catetin Signaling

Abstract

Esophageal cancer (EC) treatment remains challenging due to the disease's aggressive nature, frequent late-stage diagnosis, and the need for effective multimodal therapies with minimal side effects. Kisspeptin-10, a naturally occurring neuropeptide and known GPR54 agonist, has been shown to significantly influence tumor growth and progression. However, its specific role in EC remains poorly understood. To address this knowledge gap, we designed this study to investigate the role of Kisspeptin-10 (KP-10) and its receptor GPR54 in EC. We first assessed KP-10 expression in esophageal carcinoma tissues and cell lines using immunohistochemistry, real-time PCR, and western blot analysis. Through lentivirus transduction, we manipulated KP-10 expression and evaluated its effects on cell viability, apoptosis, migration, stemness, epithelial-mesenchymal transition (EMT), and the SIX1/Wnt/β-catenin signaling pathway. These evaluations were performed using CCK-8 assay, TUNEL assay, Transwell assay, mammosphere formation assay, and western blot analysis. Our results demonstrated significantly reduced expression of both KP-10 and GPR54 in EC samples and cell lines compared to healthy tissues. Following KP-10 overexpression in KYSE150 EC cells, we observed inhibited cell growth, promoted apoptosis, decreased cell migration, reduced cancer stem cell properties, and suppressed EMT. Furthermore, KP-10 overexpression inhibited the Wnt/β-catenin signaling pathway, an effect that was reversed by SIX1 overexpression, suggesting that KP-10's impact on this pathway is mediated through SIX1. These findings indicate that KP-10 plays a crucial role in suppressing EC progression and represents a promising therapeutic target for clinical treatment. However, more comprehensive studies are needed to fully elucidate the underlying mechanisms and explore the clinical potential of KP-10 in EC therapy.