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

BACKGROUND

Alterations in splicing factors contribute to aberrant alternative splicing (AS), which subsequently promotes tumor progression. The splicing factor polypyrimidine tract binding protein 1 (PTBP1) has been shown to facilitate cancer progression by modulating oncogenic variants. However, its specific role and underlying mechanisms in hepatocellular carcinoma (HCC) remain to be elucidated.

METHODS

PTBP1 expression was evaluated in HCC tissues and cell lines. Subsequently, cells were transfected with vectors designed for PTBP1 overexpression or downregulation. The biological function of PTBP1 was assessed and using MTS assays, colony formation assays, transwell assays, xenograft formation, tail vein injection, and orthotopic models. Transcriptome analysis was conducted to elucidate the underlying molecular mechanisms.

RESULTS

Our findings demonstrated that PTBP1 exhibited elevated expression in HCC cell lines and tissues. Furthermore, its expression positively correlated with overall and disease-free survival rates, as well as tumor grade and stage. PTBP1 knockdown reduced HCC cell proliferation, migration, and invasion and suppressed hepatocarcinoma xenograft growth and infiltration . RNA sequencing (RNA-Seq) analysis identified the AS events associated with PTBP1. PTBP1 functionally enhanced cell proliferation, invasion, and migration by modulating the AS of the microtubule-associated protein tau () gene and promoting oncogene expression. Notably, the dysregulation of MAPT splicing coincided with increased PTBP1 expression in HCC.

CONCLUSIONS

PTBP1-guided AS of the gene enhances tumorigenicity in HCC through activation of the MAPK/ERK pathways.