Abstract
Abstract Immunosuppression microenvironment allows primary tumor growth, while tumor-inherent factors that bring about immune evasion during metastasis remain elusive. Here, we observed a stronger nonsense-mediated mRNA decay (NMD) activity with a higher expression of up-frameshift protein 1 (UPF1) in colorectal cancer (CRC) metastasis than in matched primary cancer cells. In metastatic CRC SW620 cells, the higher UPF1 expression was found to arise from the increased stability of UPF1 by ubiquitin specific peptidase 10 (USP10)-mediated deubiquitination. In contrast, in primary CRC SW480 cells, autophagy promotes proteolysis of ubiquitinated UPF1 and inhibits NMD activity. Interestingly, in SW620 cells NMD selectively controlled a cluster of immune-related genes including ICAM1. Furthermore, NMD inhibition exposed SW620 cells but not SW480 cells to natural killer (NK) cell-mediated cytolysis that depended on ICAM1. Conclusion NMD activity can be recommissioned in CRC metastasis cells to escape from NK-dependent immune surveillance, and inhibiting NMD to boost anti-tumor immunity could be a novel strategy to treat CRC metastasis.
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