Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

Abstract

The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma‐secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin‐based chemotherapy may be a novel therapeutic approach for NR2F6‐overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6‐overexpressing EOC.

NR2F6 as a Prognostic Biomarker in HNSCC

“…Furthermore, without fully understanding the complete function of NR2F6 in HNSCC cells, the expression of NR2F6 within cancer cells instead of immune cells has been shown before in other solid cancer types (e.g., colon cancers) [ 24 , 25 , 26 , 27 ]. In most of these cancers, a higher NR2F6 expression was associated with a poor prognosis.…”

“…However, NR2F6 has not only been described in tumor-infiltrating lymphocytes, but also in tumor cells of different solid cancer types, e.g., hepatocellular carcinoma, ovarian cancer, cervical cancer, and colon cancer. For example, it is associated with the occurrence of pelvic lymph node metastases in cervical cancer and with poorer overall survival (OS) and cisplatin resistance in ovarian cancer [ 24 , 25 , 26 , 27 ].…”

Construction of an Immune-Associated Gene-Based Signature in Muscle-Invasive Bladder Cancer

“…NR2F6 was also defined as an intracellular immune checkpoint in tumor-infiltrating T cells and is significantly related to the survival outcomes of numerous cancers, such as head and neck squamous cell carcinoma, early-stage cervical cancer, and colon cancer [ 38 – 40 ]. Furthermore, overexpression of NR2F6 can promote the chemoresistance of epithelial ovarian cancer by activating the Notch3 signaling pathway [ 41 ]. AHNAK , also known as desmoyokin [ 42 ], is a large protein that was originally identified as a desmosomal plaque protein found at the periphery of the cytoplasmic plaque of desmosomes in the stratified squamous epithelia [ 43 ].…”

Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy

“…RO4929097 (10 μM treatment) enhanced the stem cell phenotype and increased the CDDP resistance in EOC cells by inducing Notch3 activation. RO4929097 treatment also inhibited ovarian cancer cell proliferation and increased apoptosis [ 137 ].…”

“…Probable mechanisms involved in observed anti-CSC effects of GSIs include apoptosis, cell cycle arrest, reduced survival signals (EGFR, cyclin E, NF-κB, and PI3K/Akt pathway; Bcl-xL; and Bcl-2), decreased protein levels of NICD1 mRNA, and protein expressions of Sox2 and Oct4 [ 135 , 136 , 137 , 138 , 139 , 144 , 145 , 148 , 149 ]. Most studies compared results obtained with GSIs in the presence and absence of other anticancer drugs.…”