UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

• Published in: Cell death & disease Vol. 12; no. 6; pp. 519 - 15
• Main Authors: Zhu, Congcong, Zhang, Long, Zhao, Senlin, Dai, Weixing, Xu, Yun, Zhang, Yuqin, Zheng, Hongtu, Sheng, Weiqi, Xu, Ye
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/100; 13/105; 13/109; 13/2; 13/31; 13/51; 13/89; 14/19; 14/63; 38/77; 64/60; 692/53/2422; 692/699/67/395; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Cell Biology; Cell Culture; Chemoresistance; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Topoisomerases, Type II - metabolism; Humans; Immunology; Life Sciences; Medical prognosis; Middle Aged; mRNA; Oncogenes - genetics; Oxaliplatin; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Poly-ADP-Ribose Binding Proteins - metabolism; Risk factors; RNA Helicases - metabolism; Survival; Trans-Activators - metabolism; Tumors; Zinc finger proteins
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03798-2

UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 in oxaliplatin resistance in colorectal cancer (CRC) remains unknown. In our study, UPF1 is upregulated in CRC in mRNA and protein levels and overexpression of UPF1 predicts a poor overall survival (OS) and recurrence-free survival (RFS) in CRC patients and is an independent risk factor for recurrence. UPF1 promotes chemoresistance to oxaliplatin in vitro and in vivo. UPF1-induced oxaliplatin resistance can be associated with interaction between zinc finger of UPF1 and Toprim of TOP2A and increasing phosphorylated TOP2A in a SMG1-dependent manner. Moreover, UPF1 maintains stemness in a TOP2A-dependent manner in CRC. Taken together, UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced chemoresistance to oxaliplatin in CRC, which may result from regulation of TOP2A activity and maintenance of stemness. Our findings could provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.