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Published on: March 15, 2024
EMC2 suppresses ferroptosis via regulating TFRC in nasopharyngeal carcinoma
Xianghui Chen1, Xiaoyan Wang2, Yuxia Zou3
1Shengli Clinical Medical College of Fujian Medical University, Department of Otolaryngology, Head and Neck Surgery, Fujian Provincial Hospital, Fuzhou 350001, China; Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China.
Background:
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with poorly understood underlying molecular mechanisms. Ferroptosis, a form of programmed cell death, is not fully elucidated in NPC.
Method:
We conducted quantitative proteomics to detect dysregulated proteins in NPC tissues. The levels of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC tissue microarrays were evaluated by immunohistochemistry, and the prognostic value of EMC2 was analyzed in NPC patients. The role of EMC2 in ferroptosis and carcinogenesis was determined through in vitro and in vivo experiments. Quantitative proteomics, protease inhibition, ubiquitin detection, and rescue experiments were performed to explore the mechanism of EMC2-regulated ferroptosis.
Results:
Significantly upregulated EMC2 was detected in NPC, and it was closely related to the characteristics of tumor progression. Elevated EMC2 was obviously correlated with poor survival in patients with NPC. EMC2 knockdown promoted ferroptosis, inhibiting cell viability, migration, and invasion, and enhancing the efficacy of cisplatin in NPC cells. Conversely, EMC2 overexpression contributed to ferroptosis repression, malignant progression, and reduced the efficacy of cisplatin. In addition, EMC2 knockdown suppressed xenograft tumor growth and enhanced ferroptosis in nude mice. Mechanistically, we identified transferrin receptor (TFRC) as a critical downstream protein. EMC2 interacted with TFRC and promoted its ubiquitin-proteasomal degradation. EMC2 regulated ferroptosis by mediating the level of TFRC.
Conclusions:
EMC2 suppresses ferroptosis and promotes tumor progression, and the EMC2-TFRC axis is a novel ferroptosis regulatory pathway. EMC2 is a potentially biomarker and therapeutic target for NPC.
Insights
Endoplasmic reticulum membrane protein complex 2 (EMC2) suppresses ferroptosis and promotes nasopharyngeal carcinoma (NPC) progression. Targeting the EMC2-transferrin receptor (TFRC) axis offers a new therapeutic strategy for NPC.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with incompletely understood molecular drivers.
- Ferroptosis, a regulated cell death pathway, has not been fully characterized in the context of NPC.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC.
- To elucidate the molecular mechanisms by which EMC2 influences ferroptosis and carcinogenesis in NPC.
- To evaluate EMC2 as a potential biomarker and therapeutic target for NPC.
Main Methods:
- Quantitative proteomics was employed to identify dysregulated proteins in NPC tissues.
- Immunohistochemistry was used to assess EMC2 levels in NPC tissue microarrays.
- In vitro and in vivo experiments were conducted to determine the function of EMC2 in ferroptosis and cancer progression.
- Proteomics, protease inhibition, and ubiquitin detection assays explored the EMC2-mediated ferroptosis pathway.
Main Results:
- EMC2 was significantly upregulated in NPC and correlated with tumor progression and poor patient survival.
- EMC2 knockdown induced ferroptosis, reduced NPC cell viability, migration, and invasion, and enhanced cisplatin efficacy.
- EMC2 overexpression repressed ferroptosis, promoted malignant progression, and decreased cisplatin sensitivity.
- EMC2 interacted with transferrin receptor (TFRC), promoting its degradation and thereby regulating ferroptosis.
Conclusions:
- EMC2 acts as a suppressor of ferroptosis and a promoter of NPC progression.
- The EMC2-TFRC axis represents a novel pathway regulating ferroptosis in NPC.
- EMC2 holds potential as a diagnostic biomarker and therapeutic target for nasopharyngeal carcinoma.
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