NANOG regulates epithelial–mesenchymal transition via AMPK/mTOR signalling pathway in ovarian cancer SKOV‐3 and A2780 cells

Abstract

NANOG engages with tumour initiation and metastasis by regulating the epithelial–mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). However, its role in association with pAMPKα, and its clinical significance in EOC have not been elucidated even though AMPK is known to degrade NANOG in various human cancers. Hence, we investigated the role of pAMPKα and its association with NANOG as potential prognostic biomarkers in EOC. Both NANOG and pAMPKα expression were significantly overexpressed in EOCs comparing nonadjacent normal epithelial tissues, benign tissues, and borderline tumours. NANOG overexpression was significantly associated with poor disease‐free survival (DFS) and overall survival (OS), whereas pAMPKα overexpression was associated with good DFS and OS. Importantly, multivariate analysis revealed that the combination of high NANOG and low pAMPKα expression was a poor independent prognostic factor for DFS and was associated with platinum resistance. In ovarian cancer cell lines, siRNA‐mediated NANOG knockdown diminished migration and invasion properties by regulating the EMT process via the AMPK/mTOR signalling pathway. Furthermore, treatment with AMPK activator suppressed expression of stemness factors such as NANOG, Oct4 and Sox2. Collectively, these findings established that the combination of high NANOG and low pAMPKα expression was associated with EOC progression and platinum resistance, suggesting a potential prognostic biomarker for clinical management in EOC patients.

Comparative Analysis of Primary Ovarian Cancer Cells and Established Cell Lines as a New Tool for Studies on Ovarian Cancer Cell Complexity

“…Bareiss et al documented that Sox2-expressing cells are more resistant to cell death the via apoptotic pathway caused by different chemotherapeutic agents or TRAIL [40]. Yun et al [41] demonstrated that the silencing of Nanog by siRNA caused a decreased migration activity and invasiveness of two analyzed human ovarian cancer cell lines, SKOV-3 and A2780. Furthermore, the silencing of Nanog decreased the expression of EMT markers, such as vimentin, N-cadherin, and ZEB1, and the activation of the AMPK/mTOR signaling pathway.…”

Wnt/β-catenin-driven EMT regulation in human cancers

“…For instance, FOXA2 has been in favor of decreasing cancer metastasis and it suppresses EMT [ 54 ]. Since molecular pathways regulating EMT mechanism have been somewhat well understood [ 55 ], studies have focused on EMT targeting in cancer therapy [ 52 ]. Decrease in N-cadherin and vimentin levels, and increase in E-cadherin levels can be observed after administration of β-elemene in inhibiting EMT in colorectal tumor [ 56 ].…”

The Role of Cancer Stem Cell Markers in Ovarian Cancer

“…Under physiological conditions, NANOG is responsible for the self-renewal and the pluripotency of embryonic stem cells (ESCs) [ 213 ]. In ovarian cancer, it regulates self-renewal but also EMT and chemo-resistance via the STAT3 signalling pathway [ 214 ]. Yun et al [ 214 ] demonstrated a correlation between the expression of NANOG in OCSCs and a high grade and resistance to standard chemotherapy.…”

“…In ovarian cancer, it regulates self-renewal but also EMT and chemo-resistance via the STAT3 signalling pathway [ 214 ]. Yun et al [ 214 ] demonstrated a correlation between the expression of NANOG in OCSCs and a high grade and resistance to standard chemotherapy. Sex-determining region Y-box 2 (SOX2) plays a similar role to NANOG in the physiological state [ 215 ].…”