Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer.
Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer.
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DOI：
10.1002/cac2.12184
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Huang Q
中科院分区：
文献类型：
--
作者：
Yang S;He X;Zhao J;Wang D;Guo S;Gao T;Wang G;Jin C;Yan Z;Wang N;Wang Y;Zhao Y;Xing J;Huang Q
线粒体是细胞增殖和凋亡的关键调节因子。线粒体功能的改变与炎症和肿瘤发生密切相关。本研究旨在探讨线粒体转录因子 A (TFAM)（线粒体 DNA 转录和复制的关键调节因子）是否参与结肠炎相关癌症 (CAC) 的发生和进展。通过免疫组织化学检查炎症性肠病 (IBD) 和 CAC 的组织样本中 TFAM 的表达。使用肠上皮细胞（IEC）特异性TFAM敲除小鼠（TFAM△IEC）和TFAM敲低或过表达的结直肠癌细胞（CRC）来评估TFAM在结肠炎中的作用以及CAC的发生和进展。通过分析线粒体呼吸功能和生物发生，还探讨了 TFAM 的潜在机制。 TFAM 的表达在活动性 IBD 中下调，并且与疾病活动度呈负相关。 IEC 中 TFAM 的下调是由白细胞介素 6 以信号转导器和转录激活剂 3 (STAT3)/miR-23b 依赖性方式诱导的。此外，TFAM 敲除会损害 IEC 周转，从而促进葡聚糖硫酸钠 (DSS) 诱导的小鼠结肠炎。值得注意的是，TFAM 敲除增加了小鼠对氧化偶氮甲烷/DSS 诱导的 CAC 的易感性，而 TFAM 过度表达则保护小鼠免受肠道炎症和结肠炎相关肿瘤发生的影响。相比之下，CAC 组织中 TFAM 表达上调，有助于细胞生长。此外，研究表明，β-catenin 通过 c-Myc 在 CRC 细胞中诱导 TFAM 上调。从机制上讲，TFAM 通过增加线粒体生物合成和活性来促进 IEC 和 CRC 细胞的增殖。 TFAM 在 CAC 的发生和进展中发挥双重作用，为 CAC 发病机制提供了新的理解。我们的研究揭示了 TFAM 在 CAC 的起始和进展中的相反作用，表明 TFAM 从肿瘤发生的癌前阶段的肿瘤抑制基因转变为疾病后期的癌基因。我们的数据表明，测量 TFAM 状态可能作为临床上有用的工具来识别有结肠发育不良或癌症风险的患者。相比之下，TFAM 也可能是晚期 CAC 的预后生物标志物和药理学靶点。
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). 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. 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. TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis. 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.
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影响因子：
24.5
作者：
Baker AM;Cross W;Curtius K;Al Bakir I;Choi CR;Davis HL;Temko D;Biswas S;Martinez P;Williams MJ;Lindsay JO;Feakins R;Vega R;Hayes SJ;Tomlinson IPM;McDonald SAC;Moorghen M;Silver A;East JE;Wright NA;Wang LM;Rodriguez-Justo M;Jansen M;Hart AL;Leedham SJ;Graham TA
通讯作者：
Graham TA
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
12.2
作者：
Jang, You Jin;Kim, Woon-Ki;Ko, Gwangpyo
通讯作者：
Ko, Gwangpyo
影响因子：
16.6
作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
通讯作者：
Denson, Lee A.
影响因子：
8
作者：
Li, J.;Huang, Q.;Xing, J.
通讯作者：
Xing, J.