NANOG regulates tumor metastasis via AMPK/mTOR signaling pathway in patients with epithelial ovarian cancer (252)

Abstract

<b>Objectives:</b> NANOG engages with tumor initiation and metastasis by regulating EMT (epithelial-mesenchymal transition) in epithelial ovarian cancer (EOC). However, its role in association with pAMPK and its clinical significance in EOC has not been elucidated, even though pAMPK is known to degrade NANOG in various human cancer. Therefore, here we investigated the role of pAMPK and its association with NANOG as a potential prognostic, predictive biomarker in EOC. <b>Methods:</b> Immunohistochemistry of NANOG and pAMPK in epithelial ovarian cancer tissues were performed to define the clinical significance with TMA. Moreover, ovarian cancer cell lines were used for functional studies to investigate the underlying mechanisms. <b>Results:</b> Both NANOG and pAMPK expression were significantly overexpressed in EOCs compared to nonadjacent normal epithelial tissues, benign tissues, and borderline tumors. NANOG overexpression was significantly associated with poor DFS and OS, whereas pAMPK overexpression was associated with good DFS and OS. Importantly, multivariate analysis revealed that combining high NANOG and low pAMPK expression was an independent prognostic factor for DFS and associated with poor platinum resistance. In ovarian cancer cell lines, NANOG knockdown diminished migration and invasion property by regulating the EMT process via the AMPK/mTOR signaling pathway. Furthermore, treatment of AMPK activator suppressed expression of stemness-related genes, such as <i>NANOG, Oct4</i>, and <i>Sox2</i>. <b>Conclusions:</b> Collectively, our findings established that a combination of high NANOG and low pAMPK expression was associated with EOC progression and platinum resistance, suggesting a potential predictive biomarker for clinical management in EOC patients. Also, NANOG knockdown inhibited tumor metastasis and invasion by regulating EMT via the AMPK/mTOR signaling pathway.