Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer. Issue 8 (23rd June 2021) - Yang, Shirong
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. Abstract : Our study uncover the opposite roles of TFAM in the initiation and progression of CAC, indicating that TFAM switches from tumor suppressor in the premalignant stages of tumorigenesis to oncogene at later stages of disease. Our data suggest that measuring TFAM status may serve as a clinically useful tool to identify patients at risk for colon dysplasia or cancer. In contrast, TFAM might also be a prognostic biomarker and pharmacological target for advanced CAC.