Reduced expression of UPF1 promotes tumor progression through stabilizing COX-2 mRNA in nasopharyngeal carcinoma

Nonsense-mediated mRNA decay (NMD) is conserved mRNA surveillance pathway that targeted and degraded one-third of aberrant and non-aberrant cellular transcripts. Recently, growing evidences have shown that NMD pathway is implicated in multiple cancer types. However, the activity and function of NMD in nasopharyngeal carcinoma (NPC) remains unclear. Here we demonstrated that the expression level of the core NMD factors UPF1 (up-frameshift) was significantly downregulated in NPC tissues compared with adjacent noncancerous tissues and predicted poor prognosis. Knockdown of UPF1 expression enhanced tumor growth and metastasis of NPC cells in vitro and in vivo. UPF1 down-regulated genes revealed by RNA sequencing were selectively upregulated in NPC tissues. COX-2 and PD-L1 were identified as NMD targets. UPF1 knockdown activated ERK/MAPK and JAK2/STAT3 pathways through stabilizing COX-2 in NPC cells. Importantly, co-culture with UPF1 knockdown NPC cells promotes M2 polarization and migration of macrophages, and suppressed proliferation and activation of CD8+ T cell. Our findings suggested that UPF1 expression level and NMD efficiency were impaired in NPC tissues, which contributed to tumor progression and immune modulation. Overall design: RNA was extracted from UPF1 overexpressing HK1 cells, UPF1 knockdown (UPF1-KD) 6-10B cells, UPF1 overexpressing 5-8F cells, Emetine treated 5-8F cells and their corresponding control cell lines.