NKILA represses nasopharyngeal carcinoma carcinogenesis and metastasis by NF-κB pathway inhibition

Wei Zhang,Fang Zheng,Di Huang,Herui Yao,Erwei Song,Guoying Liu,Qiannan Guo,Yanqun Xiang,Xing Yang,Jianing Chen,Linxiaoxiao Ding,Peter Hammerman

doi:10.1371/journal.pgen.1008325

Abstract

The role of long non-coding RNA (lncRNA) in the progression of Nasopharyngeal carcinoma (NPC) has not been fully elucidated. The study was designed to explore the functional role of NKILA, a newly identified lncRNA, in the progression of NPC. We performed a lncRNA expression profile microarray using four NPC and paired para-cancerous tissues. NKILA was identified as a potential functional lncRNA by this lncRNA expression profile. We used 107 paraffin-embedded NPC tissues with different TNM stages to detect the expression of NKILA and analyzed the survival data by Log-rank test and Cox regression. The role of NKILA and its underlying mechanisms in the progression of NPC were evaluated by a series of experiments in vitro and vivo by silencing or expressing NKILA. Compared with control tissues, NKILA expression was identified to be decreased in NPC tissues. Low NKILA expression was correlated with unfavorable clinicopathological features and predicted poor survival outcome in NPC patients. After adjusting for potential confounders, low expression of NKILA was confirmed to be an independent prognostic factor correlated with poor survival outcomes. Furthermore, we found that NKILA overexpression in high-metastatic-potential NPC cells repressed motile behavior and impaired the metastatic capacity in vitro and in vivo. In contrast, RNAi-mediated NKILA depletion increased the invasive motility of cells with lower metastatic potential. Further experiments demonstrated that NKILA regulated the metastasis of NPC through the NF-κB pathway. Taken together, NKILA plays vital roles in the pathogenesis of NPC. The unique histological characteristics of NPC indicate that local inflammation plays a vital role in carcinogenesis of nasopharyngeal carcinoma.

Highlights

Nasopharyngeal carcinoma (NPC), a metastasis-prone cancer, which is common in southeast Asia and southern China [1,2,3,4]
NF-κB was found to be overexpressed in most NPC tissues, and inflammatory cytokines have been observed in NPC tissues
We found that NKILA, a newly identified long non-coding RNA (lncRNA), is upregulated by inflammatory cytokines and is significantly downregulated in NPC

Summary

Introduction

Nasopharyngeal carcinoma (NPC), a metastasis-prone cancer, which is common in southeast Asia and southern China [1,2,3,4]. Several lncRNAs are aberrantly expressed or play important roles in NPC, such as HOTAIR, ENST00000438550, and AFAP1-AS1 [11,12,13,14,15]. Inflammatory cytokines have been observed in NPC tissues and can promote the susceptibility to metastasis of NPC cells via constant NF-κB activation [16,17,18], NF-κB is a pivotal link between NPC and inflammation. NKILA is an NF-κB-interacting lncRNA [21], our previously study found it can be upregulated by inflammatory cytokines in breast cancer. The role of NKILA in nasopharyngeal carcinoma remains unknown

Methods

Results

Discussion

Conclusion