| 著者 |
Zhang C, Huang Z, Su Y, Liu Y, Zhang C, Ge C, Tian W, Yang Y, Tian H.
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| Abstract |
The splicing kinase family contributes significantly to tumor progression. As a member of this family, PRPF4B has been directly implicated in oncogenic processes. However, little is known about the precise role and underlying mechanisms of PRPF4B in hepatocellular carcinoma (HCC). In this study, we found that the expression of PRPF4B was upregulated and associated with a poor prognosis in HCC patients. PRPF4B knockdown significantly suppressed HCC cell proliferation, migration, and invasion while concurrently inducing apoptosis. Knockdown of PRPF4B induced DNA damage via reactive oxygen species (ROS) accumulation, leading to cell cycle arrest at the G2/M phase. This arrest was associated with increased phosphorylation of CDC2, elevated γ-H2AX levels, and downregulation of CDC25C and cyclin B1. In addition, we found that expression of PRPF4B was upregulated in sorafenib no-responders (NR) compared with sorafenib responders (R). PRPF4B knockdown sensitizes HCC cells to sorafenib treatment. Mechanistically, we demonstrated that knockdown of PRPF4B inhibited HCC proliferation through NF-κB pathway. Furthermore, PRPF4B interacts with TIA1. Knockdown of PRPF4B promotes the expression of a specific TIA1 splice variant, leading to altered mRNA splicing that inhibits NF-κB activity. Our findings reveal that PRPF4B interacts with TIA1 and modulates its splicing. Knockdown of PRPF4B triggers ROS-dependent DNA damage, cell cycle arrest, and suppression of HCC proliferation, while enhancing sorafenib sensitivity via inhibition of the NF-κB pathway. Therefore, PPRF4B may be a potential therapeutic target for HCC treatment and sorafenib sensitization.
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