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

Cancer Communications

Tian Gao¹  Chao Jin¹  Xianli He¹  Zeyu Yan¹  Nan Wang¹  Dalin Wang²  Yongxing Wang³  Jing Zhao⁴  Gang Wang⁴  Jinliang Xing⁴  Shanshan Guo⁴  Shirong Yang⁴  Yilin Zhao⁴  Qichao Huang⁴ 

[1] Department of General Surgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710032 P. R. China;Department of Hepatobiliary Surgery Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710032 P. R. China;Department of Respiratory Medicine Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710032 P. R. China;State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. China;

关键词: colitis;    colitis‐associated cancer;    colorectal cancer;    energy metabolism;    inflammatory bowel diseases;    intestinal homeostasis;   

DOI  :  10.1002/cac2.12184

来源: DOAJ

【 摘 要 】

Abstract 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 TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial 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 IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced 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, TFAM promoted 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.

【 授权许可】

Unknown