The Role Of NLRX1 In The Development Of Colon Cancer

NLRs(Nod-like receptors)are a new family of pattern recognition receptors(PRRs),which play an important role in innate immunity through recognizing pathogen-associated molecular patterns(PAMPs).Further studies show that NLRs can not only be activated by some PAMPs but also by many damage-associated molecular pattern molecules(DAMPs).Upon the recognition of PAMPs and DAMPs they can initiate the inflammatory response and then influence the development of diseases.NLRX1 is a member of the NLR family,and it is named NLRX1 since its molecular structure includes an X domain.NLRX1 contains a signaling peptide in the N terminal that directs its location to the mitochondrial and it is also the first member of the NLR family that has been proved to be located in the mitochondria.Published results show that the NLRX1 can negatively regulate the MAVS–RIG-1 mediated antiviral response in the mitochondrial,downregulate LPS-induced TRAF6-IKK-beta signaling pathways through the interaction with TRAF6,upregulate the production of ROS induced by TNF-alpha,polyI: C and other pathogens through the NF-kB/JNK pathway,and also regulate the autophagy-associated processes by interacting with TUFM.In this project,we tried to elucidate the biological function of NLRX1 in colon cancer development using NLRX1 knockout mice and AOM+DSS induced colon cancer models.The results showed that the knock-out of NLX1 promoted the occurrence of colon cancer induced by AOM+DSS.Then we did bone marrow transplantation assay and found that the existence of NLRX1 in the stromal cells could affect the progress of colon cancer induced by AOM+DSS.Through the conditional knockout of NLRX1 in the intestinal epithelial cells,we proved that the existence of NLRX1 in the intestinal epithelial cells played an important role in the development of colon cancer.As for the underlying mechanisms,we found that apoptosis may not be affected by the depletion of NLRX1.As ROS has been reported can be regulted by NLRX1 we tested the ROS content and find the content of ROS in NLRX1 KO mouse is lower than in WT mouse.And in consistant with the ROS contene senescence in NLRX1 KO mouse is also lower in NLRX1 KO mouse and cellular proliferation is higher in NLRX1 KO mouse.In conclusion we find NLRX1 regulate senescence and proliferation through ROS and affect the development of colon cancer.Taken together,our data suggest that NLRX1 can control ROS generation,affect senescence and proliferation of the intestinal epithelial cells,and then regulate the development of colon cancer induced by AOM+DSS.