Let-7c-3p Suppresses Ovarian Cancer Progression by Targeting S100A6 and Inhibiting JAK–STAT Signaling

Background/Objectives: Ovarian cancer is one of the most lethal gynecological malignancies worldwide, largely due to late diagnosis and rapid disease progression. Increasing evidence suggests that dysregulation of calcium-binding proteins and microRNA-mediated regulatory networks contributes to ovarian cancer progression. However, the role of S100A6 and its upstream regulatory mechanisms in ovarian cancer remain poorly understood. Methods: S100A6 expression in ovarian cancer cell lines and tissues was assessed by transcriptome sequencing, qPCR, and immunohistochemistry. Functional assays (CCK-8, EdU, Transwell, wound-healing, flow cytometry) and a xenograft model were used to evaluate S100A6 effects. Bioinformatic analysis, dual-luciferase reporter assays, and rescue experiments identified upstream miRNAs. JAK–STAT involvement was examined by western blot. Survival analysis was performed using Kaplan–Meier Plotter. Results: S100A6 expression was significantly upregulated in ovarian cancer cells and tumor tissues compared with normal controls. Silencing S100A6 inhibited cell proliferation, migration, and invasion while promoting apoptosis in vitro and suppressed tumor growth in vivo. Mechanistically, S100A6 enhanced activation of the JAK–STAT signaling pathway. Further analyses identified Let-7c-3p as a direct upstream regulator of S100A6. Let-7c-3p bound to the 3′-UTR of S100A6 and suppressed its expression, thereby reversing S100A6-mediated oncogenic phenotypes and inhibiting JAK–STAT signaling. Survival analysis revealed that elevated S100A6 expression was associated with shorter progression-free survival in ovarian cancer patients. Conclusions: Our findings identify a novel Let-7c-3p/S100A6/JAK–STAT regulatory axis that promotes ovarian cancer progression. This study provides new insights into the molecular mechanisms underlying ovarian cancer development and suggests that targeting this regulatory network may represent a potential therapeutic strategy.