Abstract:Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression bei… Show more
“…We found that NR2F6 is also overexpressed in cervical squamous cell carcinoma, stomach adenocarcinoma, uterine corpus endometrial carcinoma, bladder urothelial carcinoma and breast invasive carcinoma tissue. Moreover, previous studies also indicated that Notch3 signaling is activated in these tumor types . These findings suggest that the NR2F6/Notch3 axis might also be relevant in tumor types in addition to EOC, and plays an important role in tumor progression.…”
Section: Discussionmentioning
confidence: 53%
“…The high rates and patterns of therapeutic failure seen in EOC patients are consistent with a steady accumulation of drug‐resistant CSCs . Previous reports demonstrated that the Notch3 signaling pathway is critical for the regulation of CSCs and facilitating tumor resistance to platinum . Therefore, targeting Notch3 signaling appears to be a rational and innovative approach for the treatment of EOC.…”
Section: Discussionmentioning
confidence: 71%
“…Moreover, previous studies also indicated that Notch3 signaling is activated in these tumor types. [26][27][28][29][30][31] These findings suggest that the NR2F6/Notch3 axis might also be relevant in tumor types in addition to EOC, and plays an important role in tumor progression.…”
Section: Discussionmentioning
confidence: 93%
“…24,32 Previous reports demonstrated that the Notch3 signaling pathway is critical for the regulation of CSCs and facilitating tumor resistance to platinum. [29][30][31] Therefore, targeting Notch3 signaling appears to be a rational and innovative approach for the treatment of EOC. Inhibitors of Notch signaling are presently undergoing clinical trials.…”
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.
“…We found that NR2F6 is also overexpressed in cervical squamous cell carcinoma, stomach adenocarcinoma, uterine corpus endometrial carcinoma, bladder urothelial carcinoma and breast invasive carcinoma tissue. Moreover, previous studies also indicated that Notch3 signaling is activated in these tumor types . These findings suggest that the NR2F6/Notch3 axis might also be relevant in tumor types in addition to EOC, and plays an important role in tumor progression.…”
Section: Discussionmentioning
confidence: 53%
“…The high rates and patterns of therapeutic failure seen in EOC patients are consistent with a steady accumulation of drug‐resistant CSCs . Previous reports demonstrated that the Notch3 signaling pathway is critical for the regulation of CSCs and facilitating tumor resistance to platinum . Therefore, targeting Notch3 signaling appears to be a rational and innovative approach for the treatment of EOC.…”
Section: Discussionmentioning
confidence: 71%
“…Moreover, previous studies also indicated that Notch3 signaling is activated in these tumor types. [26][27][28][29][30][31] These findings suggest that the NR2F6/Notch3 axis might also be relevant in tumor types in addition to EOC, and plays an important role in tumor progression.…”
Section: Discussionmentioning
confidence: 93%
“…24,32 Previous reports demonstrated that the Notch3 signaling pathway is critical for the regulation of CSCs and facilitating tumor resistance to platinum. [29][30][31] Therefore, targeting Notch3 signaling appears to be a rational and innovative approach for the treatment of EOC. Inhibitors of Notch signaling are presently undergoing clinical trials.…”
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.
“…Notch3 was shown to contribute to drug resistance when Notch3 knockdown combined with cisplatin chemotherapy eradicated drug‐resistant urothelial cancer cell clones. Notch3 knockdown also reduced bladder cancer progression in vivo, an observation perhaps most suggestive that Notch3 could be a suitable chemotherapeutic target for treating urothelial cancer . Notch3 expression was found to be positively correlated with the Gleason score, and high expression of Notch3 was seen in prostate cancers with high metastatic potential.…”
The family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity.
Overcoming platinum drug resistance represents a major clinical challenge in osteosarcoma (OS) treatment. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Notch signaling is implicated in regulating CSCs and tumor resistance to platinum. Thus, we attempt to investigate whether inhibiting of Notch pathway could sensitize cisplatin (CDDP) to CDDP-resistant OS cells and the underlying molecular mechanisms. OS cell lines resistant to CDDP were treated with DAPT, CDDP or combination, we present evidences that DAPT enhances the cytotoxic effect of CDDP in resistant OS by inhibiting proliferation, resulting in G0/G1 cell-cycle arrest, inducing apoptosis, and reducing motility. In addition, DAPT targeting depletes OS stem cells (OSCs), thus increasing tumor sensitivity to platinum, which indicating that a dual combination targeting both OSCs and the bulk of tumor cells are needed for tumor eradication. We also found that the combination of CDDP and DAPT exhibit additive suppression on phosphorylated AKT and ERK, contributing to the anti-cancer effects. In animal model, this combination therapy inhibits the growth and metastasis of CDDP resistant tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. Based on these results, we conclude that CDDP plus DAPT was able to sensitize CDDP-resistant human OS cells to CDDP by downregulation of Notch signaling. CDDP and DAPT combination treatment may be effective and promising for advanced OS.
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