Nuclear translocation of CDK5RAP3 regulated by NXF3 promotes the progression of gastric cancer.

[BACKGROUND] Nuclear-cytoplasmic transport proteins (NCTPs) impact the transport of proteins and RNA molecules between the nucleus and cytoplasm in tumor cells, making them promising targets for cancer therapy. Currently, the molecular mechanism and function of Nuclear RNA export factor 3 (NXF3) in gastric cancer (GC) remains unclear.

[METHODS] We used Univariate Cox regression analysis and LASSO regression analysis, Receiver Operating Characteristic (ROC) curves to construct and evaluate a NCTP prognosis risk scoring model (NCTP model). Moreover, we identified the key NCTP (NXF3) affecting GC through differential expression and prognosis analysis. Subsequently, we introduced NXF3 shRNA into GC cells to investigate the impact of NXF3 on the cell proliferation, cell migration, invasion, and cell cycle and apoptosis and tumor growth by CCK-8 assay, transwell, wound healing assay, Flow cytometry, and nude mice subcutaneous tumor in vitro and in vivo. Furthermore, we investigated the key molecules influenced by NXF3 through piRNA-Seq, RNA-Seq, RIP-Seq, IP-MS, and Nuclear-cytoplasmic transcriptomics.

[RESULTS] We constructed a prognostic risk model related to 3 NCTPs, including NXF3, GLE1 and RANGAP. The NCTP model effectively predicts the prognosis of GC patients. The low-risk group exhibited a significantly higher overall survival rate than that of the high-risk group. Notably, NXF3 is identified as a crucial NCTP in GC, and its high expression is associated with poor prognosis of GC patients. Knocking down of NXF3 significantly inhibited the proliferation, invasion, migration, cell cycle, tumor growth and induced cell apoptosis of GC cells in vitro and in vivo. Mechanistically, NXF3 modulates the cell cycle, cellular senescence related oncogenic pathways via piRNA-target network. Specifically, our findings highlighted several piRNA-related signaling pathways in GC, such as piRNA_3457319-CCND1/CDKN1A-p53, piRNA_2847077-TGFB3/TGFBR2-Cellular senescence, piRNA_448895-IGF1/PDGFRA/ACTB/MAP2K6-Rap1. Moreover, NXF3 was shown to facilitate the nuclear export of CDK5RAP3 mRNA, thereby promoting cell cycle progression and increasing cancer cell proliferation in gastric cancer.

[CONCLUSION] Our study demonstrates that NXF3 modulates cell cycle progression and promotes gastric cancer development through piRNA-related pathways and the nuclear export of CDK5RAP3 mRNA. Targeting NXF3 represents a promising strategy for developing novel therapeutic approaches for gastric cancer.