Association of C5AR1 polymorphisms with increased gastric cancer risk: mechanistic insights and therapeutic implications targeting JAK/STAT pathway.

While the pivotal role of C5a receptor 1 (C5AR1) in cancer immunity is well-established, its specific genetic and functional contributions to gastric cancer (GC) remain elucidated. This study investigates the correlation between C5AR1 polymorphisms with GC risk, alongside exploring the underlying molecular mechanisms. Genotyping was conducted utilizing a PCR-based method for identifying restriction fragment length polymorphisms (RFLP). Dual-luciferase reporter assays assessed the transcriptional activity of the rs62128435 and rs8103584 variants. Detecting the impact of C5AR1 gene knockdown on cell growth, movement, and spread in NUGC-4 and HGC-27 GC cells by CCK-8, colony formation, and Transwell assays. Western blot was utilized to discover the role of C5AR1 in the JAK/STAT signaling pathway. Individuals carrying C5AR1 rs62128435 CC and rs8103584 CC genotypes were each associated with elevated GC risk. The C5AR1 rs62128435 CC genotype and rs8103584 CC genotype altered GC risk among males, older individuals, smokers, and drinkers. Reporter assays revealed that rs62128435 C and rs8103584 T containing plasmids exhibited higher luciferase activity compared to their counterparts. C5AR1 suppressed the proliferation, colony-forming capacity, and migration of GC cells, and reduced the phosphorylation of JAK2 and STAT3, linking C5AR1 to JAK/STAT pathway regulation. This study identifies C5AR1 polymorphisms as novel risk factors for GC, linking them to regulated transcriptional activity and regulation of JAK/STAT signal. It also highlights the role of gene-environment interactions, such as smoking, alcohol status, in modulating cancer susceptibility. These findings advance understanding of GC pathogenesis and offer a foundation for personalized risk assessment and potential targeted therapies.