OBJECTIVE: To study the effect of endothelial cell-specific molecule-1 (ESM-1) on the biological behavior of cervical cancer cells and the molecular mechanism involved. STUDY DESIGN: qRT-PCR was used to detect ESM-1 expression in cervical cancer tissues and normal tissues adjacent to cancer, human normal cervical epithelial cell lines (H8), and human cervical cancer cell lines (HeLa, CaSki, C-33A, and SiHa). After silencing ESM-1 expression in C-33A and SiHa cells, MTT, flow cytometry, and Transwell assay were administered to measure cell proliferation, apoptosis, invasion, and migration, respectively. ESM-1 protein expression in tissues and PI3K-AKT-mTOR pathway related protein in cervical cancer cells were detected by western blot. RESULTS: ESM-1 expression was upregulated significantly in cervical cancer tissues and cells. Knockdown of ESM-1 inhibited the proliferation, invasion, and migration of cervical cancer cells, promoted cancer cell apoptosis, and significantly inhibited the activation of PI3K-AKT-mTOR signaling pathway. Additionally, knockdown of ESM-1 restrained the cancer-promoting effect of the PI3K activator (740Y-P) on cells. CONCLUSION: Knockdown of ESM-1 can inhibit the activation of PI3K/Akt/mTOR signaling pathway to hinder cell proliferation, invasion, and migration. Meanwhile, knockdown of ESM-1 can promote cervical cancer cell apoptosis and slow down the development of cervical cancer. Additionally, it can be used as a molecular target for the treatment and prognosis of cervical cancer. © Science Printers and Publishers, Inc.