Splicing factor PTBP1 promotes hepatocarcinogenesis via oncogenic splice-switching of MAPT

Changing splicing factors leads to abnormal alternative splicing (AS), which results in tumor progression.Splicing factor polypyrimidine tract binding proteins (PTBP1) facilitate cancer progression by modulating oncogenic variants. However, its role and mechanism in hepatocellular carcinoma (HCC) remains unclear. Our findings confirm that PTBP1 is highly expressed in HCC cells lines and tissues. Moreover, its expression correlated negatively with overallanddisease-freesurvivalrates, but inversely with tumor grade and stage. PTBP1 knockdown decreases HCC cell proliferation, migration, and invasion in vitro and inhibits hepatoma xenograft growth and infiltration in vivo. We identified PTBP1-mediated AS events and PTBP1 functionally promoted cell proliferation, invasion, and migration by altering the AS of the protein tau (MAPT) gene and promoting the oncogene expression. Strikingly, the dysregulation of MAPT splicing was paralleled by the increased expression of PTBP1 in HCC, which predicted the poor prognosis of the patients. According to additional research, AS of the MAPT gene guided by PTBP1 increases tumorigenicity in HCC by activating the MAPK/ERK pathways. In summary, our results suggest that PTBP1 plays an oncogenic role in HCC partially through the regulation of MAPT's AS, which could be a promising treatment target.