Nogo-B promotes invasion and metastasis of nasopharyngeal carcinoma via RhoA-SRF-MRTFA pathway.

Abstract

Distant metastasis remains the major cause for treatment failure in patients with nasopharyngeal carcinoma (NPC). Thus, it is necessary to investigate the underlying regulation mechanisms and potential biomarkers for NPC metastasis. Nogo-B (neurite outgrowth inhibitor B), encoded by reticulon-4, has been shown to be associated with the progression and advanced stage of several cancer types. However, the relationship between Nogo-B and NPC remains unknown. In this study, we found that higher expression of Nogo-B was detected in NPC cells and tissues. Higher expression of Nogo-B was statistically relevant to N stage, M stage, and poor prognosis in NPC patients. Further functional investigations indicated that Nogo-B overexpression could increase the migration, invasion, and metastasis ability of NPC cells in vitro and in vivo. Mechanistically, Nogo-B promoted epithelial-mesenchymal transition (EMT) and enhanced the invasive potency by interacting directly with its receptor NgR3 in NPC. Additionally, overexpression of Nogo-B could upregulate the protein levels of p-RhoA, SRF, and MRTFA. A positive relationship was found between the expression of Nogo-B and the p-RhoA in NPC patients as well as in mouse lung xenografts. Nogo-Bhigh p-RhoAhigh expression was significantly associated with N stage, M stage, and poor prognosis in NPC patients. Notably, CCG-1423, an inhibitor of the RhoA-SRF-MRTFA pathway, could reverse the invasive potency of Nogo-B and NgR3 in NPC cell lines, and decrease the expression of N-Cadherin, indicating that CCG-1423 may be a potential target drug of NPC. Taken together, our findings reveal that Nogo-B enhances the migration and invasion potency of NPC cells via EMT by binding to its receptor NgR3 to regulate the RhoA-SRF-MRTFA pathway. These findings could provide a novel insight into understanding the metastasis mechanism and targeted therapy of advanced NPC.

• Authors: Jingyi Wang, Qian Zhong, Hua Zhang, Shangxin Liu, Shibing Li, Tianliang Xia, Zhiwen Xiao, Renhui Chen, Yuchu Ye, Faya Liang, Ping Han, Xiaoming Huang
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 1 Pg. 76 (01 24 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35075114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Cadherins
• MRTFA protein, human
• Nogo Proteins
• RTN4 protein, human
• SRF protein, human
• Serum Response Factor
• Trans-Activators
• RHOA protein, human
• rhoA GTP-Binding Protein

Topics

• Animals
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Movement
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Nasopharyngeal Carcinoma (pathology)
• Nasopharyngeal Neoplasms (pathology)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Nogo Proteins (metabolism)
• Serum Response Factor (metabolism)
• Trans-Activators (metabolism)
• rhoA GTP-Binding Protein (metabolism)