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 m...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.展开更多
In order to provide the means for the design of novel rational anti-cancer drug therapies research efforts are concentrated on unravelling the molecular circuits which induce programmed cell death and block proliferat...In order to provide the means for the design of novel rational anti-cancer drug therapies research efforts are concentrated on unravelling the molecular circuits which induce programmed cell death and block proliferation of cancer cells.Modern therapeutic strategies are based on the understanding of the complexity of physiological functions such as differentiation,development,immune responses,cell-cycle arrest,DNA damage repair,apoptosis,autophagy,energy metabolism,and senescence.It has become evident that this knowledge will provide the means to target the components of the pathways involved in these processes in a specific and selective manner thus paving the way for the development of effective and personalised anti-cancer therapies.Transcription is a crucial cellular process that regulates a multitude of physiological functions,which are essential in disease progression and cellular response to therapy.Transcription factors such as the p53 tumor suppressor and the hypoxia-inducible factor-α(HIF-α) are key players in carcinogenesis and cellular response to cancer therapies.Both of these transcription factors regulate gene expression of genes involved in cell death and proliferation,in some cases cooperating towards producing the same outcome and in some others mediating opposing effects.It is thus apparent that fine tuning of the activity of these transcription factors is essential to determine the cellular response to therapeutic regimens,in other words whether tumor cells will commit to apoptosis or evade engagement with the anti-proliferative effects of drugs leading to drug resistance.Our observations support the notion that the functional crosstalk between HIF-1α and p53 pathways and thus the fine tuning of their transcriptional activity is mediated by cofactors shared between the two transcription factors such as components of the p300 co-activator multiprotein complex.In particular,there is evidence to suggest that differential composition of the co-modulatory protein complexes associated with p53 and HIF-la under diverse types of stress conditions differentially regulate the expression of distinct subsets of p53 and HIF-la target genes involved in processes such as cell cycle arrest,apoptosis,chronic inflammation,and cellular energy metabolism thereby determining the cellular fate under particular types of microenvironmental stress.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:82072722,81830070,81772935,81672340StateKey Laboratory ofCancer Biology Project,Grant/Award Number:CBSKL2019ZZ26。
文摘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.
文摘In order to provide the means for the design of novel rational anti-cancer drug therapies research efforts are concentrated on unravelling the molecular circuits which induce programmed cell death and block proliferation of cancer cells.Modern therapeutic strategies are based on the understanding of the complexity of physiological functions such as differentiation,development,immune responses,cell-cycle arrest,DNA damage repair,apoptosis,autophagy,energy metabolism,and senescence.It has become evident that this knowledge will provide the means to target the components of the pathways involved in these processes in a specific and selective manner thus paving the way for the development of effective and personalised anti-cancer therapies.Transcription is a crucial cellular process that regulates a multitude of physiological functions,which are essential in disease progression and cellular response to therapy.Transcription factors such as the p53 tumor suppressor and the hypoxia-inducible factor-α(HIF-α) are key players in carcinogenesis and cellular response to cancer therapies.Both of these transcription factors regulate gene expression of genes involved in cell death and proliferation,in some cases cooperating towards producing the same outcome and in some others mediating opposing effects.It is thus apparent that fine tuning of the activity of these transcription factors is essential to determine the cellular response to therapeutic regimens,in other words whether tumor cells will commit to apoptosis or evade engagement with the anti-proliferative effects of drugs leading to drug resistance.Our observations support the notion that the functional crosstalk between HIF-1α and p53 pathways and thus the fine tuning of their transcriptional activity is mediated by cofactors shared between the two transcription factors such as components of the p300 co-activator multiprotein complex.In particular,there is evidence to suggest that differential composition of the co-modulatory protein complexes associated with p53 and HIF-la under diverse types of stress conditions differentially regulate the expression of distinct subsets of p53 and HIF-la target genes involved in processes such as cell cycle arrest,apoptosis,chronic inflammation,and cellular energy metabolism thereby determining the cellular fate under particular types of microenvironmental stress.
