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Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target
Ping Xie1, Jun-Ping Yang1, Yun Cao2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Abstract:
Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease-free survival rates. NEDD8 expression was positively correlated with a high risk of death and positivity of lymph node metastasis. Depleted NEDD8 expression by shRNA and inhibited by specific inhibitor MLN4924 dramatically suppressed cell proliferation, cell apoptosis, cell cycle arrest, while ectopic NEDD8 exhibited opposing effects. NEDD8 affected cancer stem cell phenotypes of NPC as assessed in vitro using the cell number of side population (SP) by flow cytometry analysis, colony formation assay, sphere formation assay, and tumor initiation ability in vivo. Downregulation of NEDD8 enhanced the susceptibility of NPC cells to cisplatin and radiation. Moreover, we found that MLN4924 suppressed c-Jun degradation in human NPC cells. Taken together, this report revealed that NEDD8 may act as a novel prognostic marker and MLN4924 may serve as a promising therapeutic target for patients with NPC.
Insights
Elevated NEDD8 expression correlates with poor nasopharyngeal carcinoma (NPC) survival. Inhibiting NEDD8 with MLN4924 suppressed NPC growth and enhanced treatment sensitivity, suggesting NEDD8 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Nasopharyngeal carcinoma (NPC) is prevalent in South China with high recurrence and treatment resistance.
- The molecular basis for NPC relapse and treatment tolerance remains unclear.
- NEDD8 (Neural precursor cell expressed developmentally down-regulated 8) is implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of NEDD8 and its inhibitor MLN4924 in nasopharyngeal carcinoma.
- To evaluate NEDD8 as a prognostic marker for NPC.
- To explore MLN4924 as a potential therapeutic strategy for NPC.
Main Methods:
- Immunohistochemical staining of 197 NPC tissues.
- In vitro and in vivo experiments using shRNA to deplete NEDD8 and MLN4924 to inhibit NEDD8-activating enzyme.
- Flow cytometry, colony formation assays, sphere formation assays, and tumor initiation studies.
- Assessment of NPC cell sensitivity to cisplatin and radiation.
Main Results:
- Elevated NEDD8 expression is an unfavorable prognostic factor for NPC survival and is linked to metastasis.
- NEDD8 depletion or inhibition suppressed NPC cell proliferation, induced apoptosis, and caused cell cycle arrest.
- NEDD8 influenced cancer stem cell phenotypes and tumor initiation.
- Downregulating NEDD8 increased NPC cell sensitivity to cisplatin and radiation.
- MLN4924 inhibited c-Jun degradation in NPC cells.
Conclusions:
- NEDD8 is a potential prognostic biomarker for nasopharyngeal carcinoma.
- NEDD8 plays a significant role in NPC progression and treatment resistance.
- MLN4924 shows promise as a therapeutic agent for NPC patients.
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