Background: Nonsense-mediated mRNA decay (NMD) can degrade mRNAs with a premature termination codon (PTC), and undegraded mRNAs with PTC mutations can induce a genetic compensation response (GCR) by upregulating its compensatory genes. UPF3a refers to up-frame shift 3A (UPF3a) participating in NMD pathway and GCR. It inhibits the NMD pathway while it stimulates GCR. Notably, the role of UPF3a in cancer remains unclear.
Purpose: The identification and discovery of prognostic markers for colorectal cancer (CRC) are of great clinical significance. The aim of this study was to investigate clinical significance of UPF3a expression in CRC.
Materials and methods: UPF3a expression was examined in fresh CRC tissues and pared distant metastatic tissues using quantitative real-time PCR, Western blotting and immunohistochemistry staining. Tissue microarray immunohistochemical staining was used to study the relationship of UPF3a with clinicopathological features in 158 CRC patient samples collected from January 2008 to December 2012, and prognosis of CRC was analyzed.
Results: The expression of UPF3a was higher in metastatic tissues than that in primary sites. Moreover, high expression of UPF3a was significantly associated with TNM stage (p=0.009), liver metastasis and recurrence (p<0.001) in CRC patients. The Cancer Genome Atlas (TCGA) database showed the same trend. In CRC cells, knockdown of UPF3a led to a decline in the migration potential. Kaplan-Meier survival analysis revealed that high UPF3a expression, TNM stage were significantly associated (all P<0.01) with poor prognosis for patients. Furthermore, univariate and multivariate Cox analysis revealed that high UPF3a expression was independent risk factor for both overall survival and disease-free survival of CRC patients (all P<0.01).
Conclusion: Results showed that high levels of UPF3a could lead to aggressiveness and poor CRC prognosis. Targeted UPF3a can act as a novel and effective gene therapy for CRC patients to make a better prognosis.
Keywords: NMD pathway; TCGA; UPF3a; colorectal cancer; genetic compensation response; metastasis.