Prp19/CDC5L promotes gastric cancer via activation of the MAPK pathway-mediated homologous recombination.

Abstract

Background: Recent advances in gastric cancer (GC) treatment have not substantially improved the 5-year survival rate nor have they significantly reduced the high recurrence rate. This highlights the need for further research to explore the underlying mechanisms of GC. Cell Division Cycle 5-Like Protein (CDC5L) has been implicated in various malignant behaviors of tumors. Methods: We investigated the expression of CDC5L in gastric cancer (GC) using data from The Cancer Genome Atlas (TCGA) and clinical specimens. To explore the role of CDC5L in GC, we conducted in vitro and in vivo assays, alongside molecular mechanism studies using luciferase reporter assays, co-immunoprecipitation (CO-IP), and mass spectrometry (MS). Results: Our findings indicate a significant elevation of CDC5L in GC, with CDC5L overexpression correlating with poorer survival outcomes, advanced TNM stages, and higher pathological grades in GC patients. In vitro, interference of CDC5L markedly inhibited GC progression. We discovered that the Pre-mRNA Processing Factor 19 (Prp19) directly binds to the CDC5L promoter, enhancing its transcription and inhibiting its lysosome-mediated degradation. Additionally, CO-IP and MS assays revealed that CDC5L interacts with MAPK1, activating the MAPK signaling axis and consequently augmenting homologous recombination in GC. Conclusions: In summary, our study confirms that Prp19 upregulates CDC5L expression, which binds to MAPK1, thereby promoting GC progression via the MAPK pathway-mediated homologous recombination. Targeting CDC5L could be a promising strategy in the precision therapy of GC.