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Journal ArticleDOI: 10.1038/S41388-020-01587-3

Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications

Hui Xu1, Hui Xu2, Lei Liu2, Weilin Li3  +4 more
04 Mar 2021-Oncogene (Nature Publishing Group)-Vol. 40, Iss: 9, pp 1555-1569
Abstract: Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, however, the molecular mechanisms underlying the pathogenesis of CRC remain largely unclear. Recent studies have revealed crucial roles of transcription factors in CRC development. Transcription factors essential for the regulation of gene expression by interacting with transcription corepressor/enhancer complexes and they orchestrate downstream signal transduction. Deregulation of transcription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expression profiles play fundamental roles in multistep process of tumorigenesis, from cellular transformation, disease progression to metastatic disease. Herein, we summarized current and emerging key transcription factors that participate in CRC tumorigenesis, and highlighted their oncogenic or tumor suppressive functions. Moreover, we presented critical transcription factors of CRC, emphasized the major molecular mechanisms underlying their effect on signal cascades associated with tumorigenesis, and summarized of their potential as molecular biomarkers for CRC prognosis therapeutic response, as well as drug targets for CRC treatment. A better understanding of transcription factors involved in the development of CRC will provide new insights into the pathological mechanisms and reveal novel prognostic biomarkers and therapeutic strategies for CRC.

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Topics: Transcription factor (52%), Enhancer (52%)

9 results found

Open accessJournal ArticleDOI: 10.3390/IJMS22094764
Abstract: The replication-timing program constitutes a key element of the organization and coordination of numerous nuclear processes in eukaryotes. This program is established at a crucial moment in the cell cycle and occurs simultaneously with the organization of the genome, thus indicating the vital significance of this process. With recent technological achievements of high-throughput approaches, a very strong link has been confirmed between replication timing, transcriptional activity, the epigenetic and mutational landscape, and the 3D organization of the genome. There is also a clear relationship between replication stress, replication timing, and genomic instability, but the extent to which they are mutually linked to each other is unclear. Recent evidence has shown that replication timing is affected in cancer cells, although the cause and consequence of this effect remain unknown. However, in-depth studies remain to be performed to characterize the molecular mechanisms of replication-timing regulation and clearly identify different cis- and trans-acting factors. The results of these studies will potentially facilitate the discovery of new therapeutic pathways, particularly for personalized medicine, or new biomarkers. This review focuses on the complex relationship between replication timing, replication stress, and genomic instability.

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Topics: Replication timing (70%)

1 Citations

Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9081016
15 Aug 2021-Biomedicines
Abstract: Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.

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Topics: Tumor microenvironment (57.99%), Cancer (53%), Acquired immune system (52%) ... show more

1 Citations

Open accessJournal ArticleDOI: 10.1186/S12935-021-02317-9
Junsheng Qu1, Moyi Luo1, Jingwen Zhang1, Fang Han1  +3 moreInstitutions (1)
Abstract: Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development.

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Topics: Tumor suppressor gene (51%)

Journal ArticleDOI: 10.1038/S41388-021-02063-2
Zhuolin Li1, Yuxin He1, Yanjun Li1, Juan Li1  +5 moreInstitutions (2)
16 Oct 2021-Oncogene
Abstract: Tumor metabolic reprogramming ensures that cancerous cells obtain sufficient building blocks, energy, and antioxidants to sustain rapid growth and for coping with oxidative stress. Neurogenic differentiation factor 1 (NeuroD1) is upregulated in various types of tumors; however, its involvement in tumor cell metabolic reprogramming remains unclear. In this study, we report that NeuroD1 is positively correlated with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), in colorectal cancer cells. In addition, the regulation of G6PD by NeuroD1 alters tumor cell metabolism by stimulating the PPP, leading to enhanced production of nucleotides and NADPH. These, in turn, promote DNA and lipid biosynthesis in tumor cells, while decreasing intracellular levels of reactive oxygen species. Mechanistically, we showed that NeuroD1 binds directly to the G6PD promoter to activate G6PD transcription. Consequently, tumor cell proliferation and colony formation are enhanced, leading to increased tumorigenic potential in vitro and in vivo. These findings reveal a novel function of NeuroD1 as a regulator of G6PD, whereby its oncogenic activity is linked to tumor cell metabolic reprogramming and regulation of the PPP. Furthermore, NeuroD1 represents a potential target for metabolism-based anti-tumor therapeutic strategies.

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Topics: Pentose phosphate pathway (55%), Carcinogenesis (55%), Lipid biosynthesis (54%) ... show more

Open accessJournal ArticleDOI: 10.21037/JGO-21-376
Shanyue Tan1, Weiwei Gui1, Sumeng Wang1, Chongqi Sun1  +2 moreInstitutions (1)
Abstract: Background To construct a model that could effectively predict the prognosis of colorectal cancer (CRC) by searching for methylated-differentially expressed genes (MDEGs). Methods We identified MDEGs through four databases from Gene Expression Omnibus (GEO) and annotated their functions via bioinformatics analysis. Subsequently, after adjusting for gender, age, and grading, multivariate Cox hazard analysis was utilized to select MDEGs interrelated with the prognosis of CRC, and LASSO analysis was utilized to fit the prediction model in the training set. Furthermore, another independent dataset was harnessed to verify the effectiveness of the model in predicting prognosis. Results In total, 252 hypomethylated and up-regulated genes and 132 hypermethylated and down-regulated genes were identified, 27 of which were correlated with the prognosis of CRC, and a 10-gene prognostic model was established after LASSO analysis. The overall survival rate could be effectively grouped into different risks by the median score of this model in the training set [risk ratio (HR) =2.27, confidence interval (95% CI), 1.69-3.13, P=8.15×10-8], and the validity of its effect in predicting prognosis in CRC was verified in the validation dataset (HR =1.75, 95% CI, 1.15-2.70, P=9.32×10-3). Conclusions Our model could effectively predict the overall survival rate of patients with CRC and provides potential application guidelines for its clinically personalized treatment.

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178 results found

Open accessJournal ArticleDOI: 10.3322/CAAC.20107
Ahmedin Jemal1, Freddie Bray2, Jacques Ferlay2, Elizabeth Ward1  +1 moreInstitutions (2)
Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.

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Topics: Epidemiology of cancer (69%), Cancer (67%), Preventive healthcare (63%) ... show more

51,138 Citations

Open accessJournal ArticleDOI: 10.3322/CAAC.21262
Abstract: Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.

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Topics: Causes of cancer (67%), Cancer (66%), Breast cancer (59%) ... show more

21,062 Citations

Journal ArticleDOI: 10.1038/NRM909
David E. Levy1, James E. Darnell1Institutions (1)
Abstract: Extracellular proteins bound to cell-surface receptors can change nuclear gene expression patterns in minutes, with far-reaching consequences for development, cell growth and homeostasis. The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways. In addition to several roles in normal cell decisions, dysregulation of STAT function contributes to human disease, making the study of these proteins an important topic of current research.

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Topics: STAT6 (61%), Protein inhibitor of activated STAT (61%), STAT protein (59%) ... show more

2,533 Citations

Journal ArticleDOI: 10.1038/NCB0502-E131
Eitan Shaulian1, Michael Karin2Institutions (2)
Abstract: The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death. Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these processes were recently identified. Interestingly, the growth-promoting activity of c-Jun is mediated by repression of tumour suppressors, as well as upregulation of positive cell cycle regulators. Mostly, c-Jun is a positive regulator of cell proliferation, whereas JunB has the converse effect. The intricate relationships between the different Jun proteins, their activities and the mechanisms that mediate them will be discussed.

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Topics: JUNB (59%), Regulator (56%), Transcription factor (54%) ... show more

2,463 Citations

Journal ArticleDOI: 10.1038/35085068
Bernhard M. Mayr1, Marc Montminy1Institutions (1)
Abstract: The transcription factor CREB -- for 'cyclic AMP response element-binding protein' -- functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways?

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Topics: ATF/CREB (71%), CREB (68%), CRTC2 (67%) ... show more

2,314 Citations

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