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

Jingyi Wang,Ping Han,Hua Zhang,Shangxin Liu,Zhiwen Xiao,Yuchu Ye,Shibing Li,Renhui Chen,Qian Zhong,Faya Liang,Xiaoming Huang,Tianliang Xia

doi:10.1038/s41419-022-04518-0

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.

Highlights

Nasopharyngeal carcinoma (NPC), a type of malignant carcinoma originating from epithelial cells, is endemic in Southeast Asia [1,2,3]
neurite outgrowth inhibitor (Nogo)-A and Nogo-C showed little difference in the mRNA levels between NPC cell lines and NPECs (Supplementary Fig. 1A), while higher Nogo-B mRNA expression levels were found in NPC cell lines (Fig. 1B)
These results indicated that Nogo-B was upregulated in NPC cell lines and tissues

Summary

Introduction

Nasopharyngeal carcinoma (NPC), a type of malignant carcinoma originating from epithelial cells, is endemic in Southeast Asia [1,2,3]. With improvement in the diagnosis level and the development of radiotherapy technology, the local control and overall survival rate of NPC have markedly improved; distant metastasis remains the main reason for treatment failure [4]. Among the NPC patients with recurrence, distant metastasis might account for 40–50% within the first year and 80–97% within 5 years after treatment, respectively [6,7,8,9]. Current evaluations of the severity and therapeutic regimen of NPC patients are mainly based on TNM staging from clinical imaging examinations [10]. Web-based calculators had been used to predict the personalized conditional risk of recurrence in NPC, but the evaluation system remains insufficient to accurately predict the risk of distant metastasis [11]. The underlying mechanisms and potential biomarkers of NPC metastasis need to be identified, hopefully facilitating the prediction of metastasis and prognosis of NPC and even the development of novel therapeutic targets

Methods

Results

Conclusion