Objective:While the upregulation of cytochrome P450 family 24 subfamily A member 1(CYP24Al)gene expression has been reported in colon cancer,its role in tumorigenesis remains largely unknown.In this study,we aimed to investigate the involvement of CYP24Al in Wnt pathway regulation via the nuclear factor kappa B(NF-κB)pathway.Methods:The human colon cancer cell lines HCT-116 and Caco-2 were subjected to stimulation with interleukin-6(IL-6)as well as tumor necrosis factor alpha(TNF-a),with subsequent treatment using the NF-κB pathway-specific inhibitor ammonium pyrrolidinedithiocarbamate(PDTC).Furthermore,CYP24Al expression was subjected to knockdown via the use of small interfering RNA(siRNA).Subsequently,NF-KB pathway activation was determined by an electrophoretic mobility shift assay,and the transcriptional activity of β-catenin was determined by a dual-luciferase reporter assay.A mouse ulcerative colitis(UC)-associated carcinogenesis model was established,wherein TNF-αand the NF-κB pathway were blocked by anti-TNF-a monoclonal antibody and NF-κB antisense oligonucleotides,respectively.Then the tumor size and protein level of CYP24A1 were determined.Results:IL-6 and TNF-α upregulated CYP24A1 expression and activated the NF-κB pathway in colon cancer cells.PDTC significantly inhibited this increase in CYP24A1 expression.Additionally,knockdown of CYP24A1 expression by siRNA could partially antagonize Wnt pathway activation.Upregulated CYP24A1 expression was observed in the colonic epithelial cells of UC-associated carcinoma mouse models.Anti-TNF-a monoclonal antibody and NF-κB antisense oligonucleotides decreased the tumor size and suppressed CYP24A1 expression.Conclusion:Taken together,this study suggests that inflammatory factors may increase CYP24A1 expression via NF-κB pathway activation,which in turn stimulates Wnt signaling.

Xue-qi CHEN;Jia-yu MAO;Chun-saier WANG;Wen-bin LI;Tao-tao HAN;Ke LV;Jing-nan LI

Department of Medical Ultrasound,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Science,Beijing 100730,China;Department of Critical Care Medicine,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Science,Beijing 100730,China;Department of Gastroenterology,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;Department of Gastroenterology,Beijing Hospital,National Center of Gerontology,Institute of Geriatrics Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China;Department of Gastroenterology,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Science;Key Laboratory of Gut Microbiota Translational Medicine Research,Chinese Academy of Medical Science,Beijing 100730,China;Key Laboratory of Gut Microbiota Translational Medicine Research,Chinese Academy of Medical Science,Beijing 100730, China

当代医学科学(英文)

[1]Xue-qi CHEN;Jia-yu MAO;Chun-saier WANG;Wen-bin LI;Tao-tao HAN;Ke LV;Jing-nan LI-.CYP24A1 Involvement in Inflammatory Factor Regulation Occurs via the Wnt Signaling Pathway)[J].当代医学科学(英文),2022(05):1022-1032

Occurs,CYP24Al,pyrrolidinedithiocarbamate,Upregulated

CYP24A1,Involvement,Inflammatory,Factor,Regulation,via,Wnt,Signaling,Pathway,Objective,While,upregulation,cytochrome,P450,subfamily,member,expression,has,been,reported,cancer,its,role,tumorigenesis,remains,largely,unknown,this,study,aimed,investigate,involvement,pathway,nuclear,kappa,Methods,human,lines,HCT,Caco,were,subjected,stimulation,interleukin,well,necrosis,alpha,subsequent,treatment,using,specific,inhibitor,ammonium,PDTC,Furthermore,was,knockdown,small,interfering,siRNA,Subsequently,KB,activation,determined,by,electrophoretic,mobility,shift,assay,transcriptional,activity,catenin,dual,luciferase,reporter,mouse,ulcerative,colitis,UC,associated,carcinogenesis,established,wherein,blocked,monoclonal,antibody,antisense,oligonucleotides,respectively,Then,size,protein,level,Results,upregulated,activated,cells,significantly,inhibited,increase,Additionally,could,partially,antagonize,observed,colonic,epithelial,carcinoma,models,Anti,decreased,suppressed,Conclusion,Taken,together,suggests,that,inflammatory,factors,may,which,turn,stimulates,signaling

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