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Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer

查看全文 作　　者：Shirong [1,2]Yang;Xianli [2]He;Jing [1]Zhao;Dalin [3]Wang;Shanshan [1]Guo;Tian [2]Gao;Gang [1]Wang;Chao [2]Jin;Zeyu [2]Yan;Nan [2]Wang;Yongxing [4]Wang;Yilin [1]Zhao;Jinliang [1]Xing;Qichao [1]Huang 高影响力作者 机构地区：[1]State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology,Fourth Military Medical University,Xi’an,Shaanxi 710032,P.R.China;[2]Department of General Surgery,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,P.R.China;[3]Department of Hepatobiliary Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,P.R.China;[4]Department of Respiratory Medicine,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710032,P.R.China高影响力机构 出　　处：《Cancer Communications》索引2021年第41卷第8期,共20页高影响力期刊 基　　金：National Natural Science Foundation of China,Grant/Award Numbers:82072722,81830070,81772935,81672340;StateKey Laboratory ofCancer Biology Project,Grant/Award Number:CBSKL2019ZZ26。 摘　　要：Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis. 关 键 词：colitis colitis-associated cancer colorectal cancer energy metabolism inflammatory bowel diseases intestinal homeostasis mitochondrial transcription factor A(TFAM)
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