A novel tRNA-Derived Fragment, tRF-23-Z87HFK8SDZ inhibits malignant progression of pancreatic cancer through mediating IRS1.

[BACKGROUND] Transfer RNA-derived fragments (tRFs) have emerged as significant actors in cancer progression. Nevertheless, their functions in pancreatic cancer stay poorly understood. This work focuses on the role of tRF-23-Z87HFK8SDZ (tRF-23), a downregulated fragment in pancreatic cancer, and its potential tumor-suppressive functions through the regulation of IRS1.

[METHODS] RNA sequencing was performed on cancerous and adjacent non-cancerous tissues from pancreatic cancer patients to identify differentially expressed tRFs. RT-qPCR, Kaplan-Meier survival analysis, and various in vivo and in vitro functional assays were performed to assess tRF-23 expression, its effects on cellular processes, and its regulation of IRS1. Dual-luciferase and RNA immunoprecipitation assays proved the interaction between tRF-23 and IRS1.

[RESULTS] tRF-23 was considerably downregulated in pancreatic cancer tissues and cells. Lower tRF-23 expression was correlated with poor patient survival. Overexpression of tRF-23 inhibited cell viability, proliferation, and migration, while advancing cell cycle arrest and apoptosis in pancreatic cancer cells. In vivo, tRF-23 reduced tumor growth in a subcutaneous mouse model. tRF-23 directly targeted IRS1, downregulating its protein and mRNA levels, and IRS1 overexpression partially rescued these effects.

[CONCLUSION] tRF-23 suppresses the malignant progression of pancreatic cancer by downregulating IRS1. These findings suggest that the tRF-23/IRS1 axis could act as a prospective therapeutic target in pancreatic cancer.