Study On The Effect Of Prion Protein On Inflammatory Response By Activating NF-?B

Recent studies suggested cellular prion protein?PrP?may involve in tumor formation,metastasis and chemo-resistance and may also play an important role in regulating inflammatory responses.In this study,we applied Dextran Sulfate Sodium?DSS?to induce colitis-associated colorectal cancer in three genotypes of mice:wild-type mice?WT?,PrP-knockout mice(PrP^-/-)and PrP-overexpressing mice?Tga20?,and investigated the role of PrP in NF-kappa B activation.In this study,mice with three genotypes were treated with oral administration of1.5%DSS for 3 cycles,and their body weight change and tumor formation were compared.The severity of inflammation was assessed by the Histological Activity Index?HAI?and the expression of inflammatory factors of colon tissues from these mice were tested by Reverse Transcription quantitative PCR.The bone marrow-derived macrophages?BMDMs?from different mice and PrP knockdown human colon cancer cells HT29 were induced with Lipopolysaccharide?LPS?to compare the activation of NF-?B.The study found that compared with WT and Tga20 mice,the weight of PrP^-/-mice decreased significantly after administration of DSS,and PrP^-/-mice grew more tumors.After HE staining,it was found that the HAI score of PrP^-/-mice was significantly higher than that of Tga20 mice,and the inflammatory cytokines TNF-?and IL-1?of PrP^-/-mice were significantly higher than that of Tga20 mice.For BMDMs from PrP^-/-mice,the peak of NF-?B nuclear translocation was delayed from30 minutes to 120 minutes,and the early peak was restored by PrP overexpression.For HT29 cells,NF-?B translocation was also delayed in case of PrP knocking down and LPS-induced inflammation was increased.NF-?B translocation usually occurred30-60 minutes after stimulation,while it appeared 150 minutes after stimulation in PrP-knockdown HT29 cells.In conclusion,PrP knockout could cause more severe inflammatory response in vivo and delay the peak of NF-?B translocation in vitro,and reoverexpression of PrP could reverse this response.Therefore,PrP may be involved in tumor formation by regulating the inflammatory response via delaying NF-?B translocation.