Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis

Hirano, Takehiro; Hirayama, Daisuke; Wagatsuma, Kohei; Yamakawa, Tsukasa; Yokoyama, Yoshihiro; Nakase, Hiroshi

doi:10.3390/ijms21093062

Cited by 86 publications

(69 citation statements)

References 82 publications

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“…NF-κB as a transcription factor is commonly upregulated in cancer cells and is implicated in the increased synthesis of inflammatory cytokines ( Liu et al, 2020 ). NF-κB not only activates genes associated with cancer cell proliferation, invasion and metastasis, but also induces the expression of inflammatory cytokines and chemokines (e.g., IL-6 and COX-2) ( Hirano et al, 2020 ). NF-κB can crosstalk with STAT3 at multiple levels, and is also a critical target molecule for anti-tumor therapy ( Degoricija et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Paeonol Suppresses Proliferation and Motility of Non-Small-Cell Lung Cancer Cells by Disrupting STAT3/NF-κB Signaling

Zhang

Chen

et al. 2020

Front. Pharmacol.

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Background: Targeting inflammatory microenvironment is a promising anti-tumor strategy. Paeonol is a phenolic compound with effective anti-inflammatory and anti-tumor properties. However, the effects of paeonol on non-small cell carcinoma (NSCLC) have not been fully investigated. Here, we evaluated the effects of paeonol on proliferation and metastasis of NSCLC and elucidated the underlying mechanisms.Methods: The effects of paeonol on inflammatory cytokines were determined by cell proliferation and ELISA assays. Assays of wound healing, single cell migration and perforation invasion were used to evaluate migration and invasion of NSCLC cells. Expression of marker proteins in epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) family enzymes were detected by Western blot assays. Nude mouse A549 cells transplantation tumor model was used to study the anti-lung cancer effects of paeonol in vivo. TUNEL stanining were used to detect the apoptosis of tumor cells in A549 lung cancer mice, and Ki67 analysis was used to detect the proliferation of tumor cells in A549 lung cancer mice. Immunohistochemistry was used to detect the effects of paeonol on signaling molecules in tumor tissues.Results: Paeonol inhibited A549 cancer cell migration and invasion in vitro. Paeonol inhibited secreaion of inflammatory cytokines in A549 cells, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and transforming growth factor (TGF)-β. Paeonol altered the expression of marker proteins involved in EMT and MMP family enzymes. In addition, paeonol inhibited the transcriptional activity of nuclear factor-κB (NF-κB) and phosphorylation of signal transducers and activators of transcription 3 (STAT3). Paeonol inhibited the growth of A549 cells transplanted tumors in nude mice.Conclusion: Paeonol potently inhibited NSCLC cell growth, migration and invasion associated with disruption of STAT3 and NF-κB pathways, suggesting that it could be a promising anti-metastatic candidate for tumor chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Paeonol Suppresses Proliferation and Motility of Non-Small-Cell Lung Cancer Cells by Disrupting STAT3/NF-κB Signaling

Zhang

Chen

et al. 2020

Front. Pharmacol.

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“…35 Among the involved pathways, the aberrant stimulation of NF-κB have been detected in intestinal epithelial cells from both IBD and CRC, 36 and can contribute to inflammation-associated tissue injury 37 as well as tumor cell proliferation via the overexpression of angiogenesis-related genes. 33 In our present study, we have identified a 7-NF-κB-related gene signature (FOS, CCL4, Considering the crucial role in UC and CAC, there is no doubt that the TNF signaling via NF-κB pathway could be highly enriched in CAC samples with significance in our study. The activation of the NF-κB pathway upregulates the expression of pro-inflammatory cytokines and adhesion factors, inhibits the production of apoptotic factors, and promotes tumor angiogenesis and metastasis.…”

mentioning

confidence: 50%

“…The consistent action of inflammatory on intestinal mucosa has been elucidated to predispose UC to CAC by multiple tumor-related genetic changes in intestinal epithelial cells. 32 , 33 Watanabe et al generated 20 discriminator genes to predict the development of CAC among the UC patients, including the cancer-related genes CYP27B1, RUNX3, SAMSN1, EDIL3, NOL3, CXCL9, ITGB2 , and LYN . Nevertheless, they did not distinguish the active UC patients from those in remission.…”

Section: Discussionmentioning

confidence: 99%

<p>A Seven-NF-κB-Related Gene Signature May Distinguish Patients with Ulcerative Colitis-Associated Colorectal Carcinoma</p>

Wei

Tian

et al. 2020

PGPM

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Purpose Ulcerative colitis (UC) patients have an increased risk of colorectal cancer (CRC), and compared with sporadic CRC, ulcerative colitis-associated colorectal cancer (CAC) is more aggressive with a worse prognosis. This study aimed to identify a gene signature to predict the risk of CAC for patients with UC in remission. Patients and Methods Series of quiescent UC-related transcriptome data obtained from the Gene Expression Omnibus (GEO) data set were divided into a training set and a validation set. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and \Weighted Correlation Network Analysis (WGCNA) combined with protein–protein interaction (PPI) analysis were used to identify the pathways and gene signatures related to tumorigenesis among quiescent UC patients. A generalized linear model (GLM) of Poisson regression based on the training set was applied to estimate the diagnostic power of the gene signature in our validation set. Results The tumor necrosis factor (TNF) signaling via NF-κB pathway was significantly augmented with the highest normalized enrichment score (NES). The genes in the brown module from WGCNA have shown a significant correlation with CAC (Pearson coefficient = 0.83, p = 6e-06). A subset of NF-κB related genes ( FOS, CCL4, CXCL1, MYC, CEBPB, ATF3 , and JUNB ) were identified with a relatively higher expression level in CAC samples. The diagnostic value of this 7-gene biomarker was estimated by the receiver operating characteristic (ROC) curve with an area under the ROC curve (AUC) at 0.82 (p<0.0001, 95% CI: 0.7098–0.9400) in the validation cohort. Conclusion In summary, the increased expression of this seven-NF-κB-related gene signature may act as a powerful index for tumorigenesis prediction among patients with UC in remission.

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“…The ability to mount an appropriate inflammatory response is part of our key defence mechanisms against pathogens and disease; however, it is when inflammation becomes chronic that problems can arise, including acting as a trigger for tumorigenesis [ 105 ]. Chronic inflammation, such as that seen in inflammatory bowel disease (IBD) and ulcerative colitis (UC), is driven by inflammatory mediators such as nuclear factor (NF)-κB and signal transducer and activator of transcription 3 (STAT3), cytokines such as interleukin 6 (IL-6) and prostaglandins, and has been linked to an increased risk of developing cancer [ 106 , 107 , 108 , 109 , 110 ]. Using a model of Rnf20 heterozygous mice to drive depleted H2Bub1, as well as human samples of UC and colorectal cancer, Tarcic and colleagues have shown that loss of H2Bub1 creates a tumour promoting microenvironment in the colon centred on the chronic inflammatory response [ 21 ].…”

Section: Global Loss Of H2bub1 In Human Malignancymentioning

confidence: 99%

Histone Monoubiquitination in Chromatin Remodelling: Focus on the Histone H2B Interactome and Cancer

Marsh

Yue

Dickson

2020

Cancers

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Chromatin remodelling is a major mechanism by which cells control fundamental processes including gene expression, the DNA damage response (DDR) and ensuring the genomic plasticity required by stem cells to enable differentiation. The post-translational modification of histone H2B resulting in addition of a single ubiquitin, in humans at lysine 120 (K120; H2Bub1) and in yeast at K123, has key roles in transcriptional elongation associated with the RNA polymerase II-associated factor 1 complex (PAF1C) and in the DDR. H2Bub1 itself has been described as having tumour suppressive roles and a number of cancer-related proteins and/or complexes are recognised as part of the H2Bub1 interactome. These include the RING finger E3 ubiquitin ligases RNF20, RNF40 and BRCA1, the guardian of the genome p53, the PAF1C member CDC73, subunits of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodelling complex and histone methyltransferase complexes DOT1L and COMPASS, as well as multiple deubiquitinases including USP22 and USP44. While globally depleted in many primary human malignancies, including breast, lung and colorectal cancer, H2Bub1 is selectively enriched at the coding region of certain highly expressed genes, including at p53 target genes in response to DNA damage, functioning to exercise transcriptional control of these loci. This review draws together extensive literature to cement a significant role for H2Bub1 in a range of human malignancies and discusses the interplay between key cancer-related proteins and H2Bub1-associated chromatin remodelling.

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Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis

Cited by 86 publications

References 82 publications

Paeonol Suppresses Proliferation and Motility of Non-Small-Cell Lung Cancer Cells by Disrupting STAT3/NF-κB Signaling

Paeonol Suppresses Proliferation and Motility of Non-Small-Cell Lung Cancer Cells by Disrupting STAT3/NF-κB Signaling

<p>A Seven-NF-κB-Related Gene Signature May Distinguish Patients with Ulcerative Colitis-Associated Colorectal Carcinoma</p>

Histone Monoubiquitination in Chromatin Remodelling: Focus on the Histone H2B Interactome and Cancer

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