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

<b>Background:</b> 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. <b>Methods:</b> 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 <i>in vitro</i> and <i>in vivo</i> assays, alongside molecular mechanism studies using luciferase reporter assays, co-immunoprecipitation (CO-IP), and mass spectrometry (MS). <b>Results:</b> 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. <i>In vitro</i>, 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. <b>Conclusions:</b> 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.