Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor–stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1−/− mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1−/− mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1−/− mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1−/− mice showed increased accumulation of Ly6G+Ly6C−CD11b+ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.

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Grape Pomace Inhibits Colon Carcinogenesis by Suppressing Cell Proliferation and Inducing Epigenetic Modifications in an AOM/DSS Mouse Model

Current Developments in Nutrition ◽

10.1093/cdn/nzaa044_057 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 358-358

Author(s):

Qiyu Tian ◽

Xhixin Xu ◽

Xiaofei Sun ◽

Jeanene Deavila ◽

Min Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Wnt Signaling ◽

Activity Index ◽

Control Diet ◽

Disease Activity Index ◽

Experimental Period ◽

Dna Demethylation ◽

Grape Pomace ◽

Protective Effects

Abstract Objectives Grape pomace (GP), a by-product of the wine and juice industry, is rich in bioflavonoids and dietary fibers. We hypothesized that grape pomace has protective effects against colitis-associated colorectal cancer (CRC). Methods Nine-week-old female mice were fed a control diet (CON) or CON with 5% grape pomace (GP) for 2 weeks, when mice were subjected to azoxymethane (AOM)/dextran sulfate sodium (DSS) for colorectal cancer (CRC) induction. All animals were received 1% DSS in drinking water for 7 days followed by a 21-day recovery in a 3-cycle experimental period, while receiving their respective diet. Results GP supplementation ameliorated the disease activity index (DAI) score, reduced tumor number, tumor size and pathological scores in AOM/DSS treated mice. Furthermore, dietary GP suppressed colonic expression of inflammatory cytokines, IL-1β and TNF-α, and inhibited NF-κB inflammatory signaling. Colorectal inflammation is known to enhance Wnt signaling and cell proliferation. In agreement, the content of β-catenin, a key downstream mediator of Wnt signaling, was reduced so for the expression of Cyclin D1 phosphorylation and content of p53 and PCNA level in GP-fed mice. In addition, GP reduced the expression of ALDH1, a marker of cell stemness, and increased the expression of Cdx2, a key transcription factor initiating epithelial cell differentiation. Consistently, DNA methylation of the promoter region of Cdx2 gene and hypermethylation of GpG island methylator phenotype (CIMP), which commonly occurs during CRC carcinogenesis, was alleviated in GP group. Conclusions GP supplementation suppressed colitis-associated CRC carcinogenesis associated with the suppression of inflammation and cell proliferation and the enhancement of DNA demethylation in Cdx2 and CIMP genes in the colon. Funding Sources USDA-NIFA 2018–67,017-27,517.

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The Gut Microbiome Modulates Colon Tumorigenesis

mBio ◽

10.1128/mbio.00692-13 ◽

2013 ◽

Vol 4 (6) ◽

Cited By ~ 314

Author(s):

Joseph P. Zackular ◽

Nielson T. Baxter ◽

Kathryn D. Iverson ◽

William D. Sadler ◽

Joseph F. Petrosino ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Gut Microbiome ◽

Tumor Development ◽

Tumor Formation ◽

Normal Functioning ◽

Operational Taxonomic Units ◽

Tumor Bearing ◽

Colon Tumorigenesis

ABSTRACT Recent studies have shown that individuals with colorectal cancer have an altered gut microbiome compared to healthy controls. It remains unclear whether these differences are a response to tumorigenesis or actively drive tumorigenesis. To determine the role of the gut microbiome in the development of colorectal cancer, we characterized the gut microbiome in a murine model of inflammation-associated colorectal cancer that mirrors what is seen in humans. We followed the development of an abnormal microbial community structure associated with inflammation and tumorigenesis in the colon. Tumor-bearing mice showed enrichment in operational taxonomic units (OTUs) affiliated with members of the Bacteroides, Odoribacter, and Akkermansia genera and decreases in OTUs affiliated with members of the Prevotellaceae and Porphyromonadaceae families. Conventionalization of germfree mice with microbiota from tumor-bearing mice significantly increased tumorigenesis in the colon compared to that for animals colonized with a healthy gut microbiome from untreated mice. Furthermore, at the end of the model, germfree mice colonized with microbiota from tumor-bearing mice harbored a higher relative abundance of populations associated with tumor formation in conventional animals. Manipulation of the gut microbiome with antibiotics resulted in a dramatic decrease in both the number and size of tumors. Our results demonstrate that changes in the gut microbiome associated with inflammation and tumorigenesis directly contribute to tumorigenesis and suggest that interventions affecting the composition of the microbiome may be a strategy to prevent the development of colon cancer. IMPORTANCE The trillions of bacteria that live in the gut, known collectively as the gut microbiome, are important for normal functioning of the intestine. There is now growing evidence that disruptive changes in the gut microbiome are strongly associated with the development colorectal cancer. However, how the gut microbiome changes with time during tumorigenesis and whether these changes directly contribute to disease have not been determined. We demonstrate using a mouse model of inflammation-driven colon cancer that there are dramatic, continual alterations in the microbiome during the development of tumors, which are directly responsible for tumor development. Our results suggest that interventions that target these changes in the microbiome may be an effective strategy for preventing the development of colorectal cancer.

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miR-378a-5p inhibits the proliferation of colorectal cancer cells by downregulating CDK1

10.21203/rs.3.rs-127801/v1 ◽

2020 ◽

Author(s):

Kai Li ◽

Jieling zhang ◽

Mingkang Zhang ◽

Yaohua Wu ◽

xinyu Lu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Function ◽

Tumor Formation ◽

Luciferase Reporter ◽

Mouse Tumor ◽

The Impact ◽

Pathological Tissues

Abstract Background MicroRNAs (miRNAs) exerts a vital part in tumor occurrence.The role of miR-378a-5p and CDK1 in colorectal cancer (CRC) was investigated in this study. Methods The investigation of TCGA database and the detection of miR-378a-5p expression in colorectal cancer pathological tissues and colorectal cancer cell lines were performed by using qRT-PCR. We conducted cell function experiments (CCK-8, EDU, Colony formation assay, Wound healing assay, Transwell assay, Cell apoptosis detection, Cell cycle detection) and nude mouse tumor formation experiments to evaluate the effects of miR-378a-5p on proliferation, metastasis, The impact of invasion to explore the role of miR-378a-5p in vivo and in vitro. Then, through the TCGA database, immunohistochemistry of pathological tissues, and cell function experiments, the role of the target gene CDK1 of miR-378a-5p verified by database prediction and dual luciferase reporter gene experiments in colorectal cancer was explored. Finally, whether up-regulation of CDK1 restores the inhibitory effect of overexpression of miR-378a-5p on the proliferation of CRC cells is studied by overexpression of CDK1. Results Bioinformatics analysis showed significant downregulation of miR-378a-5p level within colorectal cancer (CRC). Cell function experiments and tumor xenograft mouse models confirmed the low expression of miR-378a-5p within CRC tissues, which indicated the tumor suppression role of miR-378a-5p within CRC. For better exploring the regulation of miR-378a-5p in CRC, we predicted and validated cell cycle-dependent protein kinase 1 (CDK1) to be the miR-378a-5p target geneand found that miR-378a-5p suppressed CRC cell proliferation by targeting CDK1. Conclusion To sum up, results in this work discover the mechanism of miR-378a-5p in retarding CRC cell proliferation through suppressing CDK1 expression, and it may become a possible therapeutic target to treat CRC.

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STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22147695 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7695

Author(s):

Yael Delgado-Ramirez ◽

Itzel Baltazar-Perez ◽

Yamileth Martinez ◽

Blanca E. Callejas ◽

Itzel Medina-Andrade ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Tumor Development ◽

Suppressor Cells ◽

Tumor Formation ◽

Intestinal Cell ◽

Arginase 1 ◽

Colorectal Cancer Progression ◽

Oxide Synthase

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.

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Psychological Correlates of Self-reported Disease Activity in Ankylosing Spondylitis

The Journal of Rheumatology ◽

10.3899/jrheum.090476 ◽

2010 ◽

Vol 37 (4) ◽

pp. 829-834 ◽

Cited By ~ 29

Author(s):

TAMAR F. BRIONEZ ◽

SHERVIN ASSASSI ◽

JOHN D. REVEILLE ◽

CHARLES GREEN ◽

THOMAS LEARCH ◽

...

Keyword(s):

New York ◽

Ankylosing Spondylitis ◽

Disease Activity ◽

Activity Index ◽

Disease Activity Index ◽

Multivariate Regression Analysis ◽

Passive Coping ◽

Psychological Variables ◽

Psychological Measures

Objective.To investigate the role of psychological variables in self-reported disease activity in patients with ankylosing spondylitis (AS), while controlling for demographic and medical variables.Methods.Patients with AS (n = 294) meeting modified New York criteria completed psychological measures evaluating depression, resilience, active and passive coping, internality, and helplessness. Demographic, clinical, and radiologic data were also collected. Univariate and multivariate analyses were completed to determine the strength of the correlation of psychological variables with disease activity, as measured by the Bath AS Disease Activity Index (BASDAI).Results.In the multivariate regression analysis, the psychological variables contributed significantly to the variance in BASDAI scores, adding an additional 33% to the overall R-square beyond that accounted for by demographic and medical variables (combined R-square 18%). Specifically, arthritis helplessness and depression accounted for the most significant portion of the variance in BASDAI scores in the final model.Conclusion.Arthritis helplessness and depression accounted for significant variability in self-reported disease activity beyond clinical and demographic variables in patients with AS. These findings have important clinical implications in the treatment and monitoring of disease activity in AS, and suggest potential avenues of intervention.

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Sevoflurane inhibits malignant progression of colorectal cancer via hsa_circ_0000231-mediated miR-622

Journal of Biological Research-Thessaloniki ◽

10.1186/s40709-021-00145-6 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Jingpeng Wang ◽

Shuyuan Li ◽

Gaofeng Zhang ◽

Huihua Han

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cell Apoptosis ◽

Volatile Anesthetic ◽

Tumor Formation ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Circular Rnas

Abstract Background Sevoflurane (Sev), a commonly used volatile anesthetic, has been reported to inhibit the process of colorectal cancer (CRC). Circular RNAs (circRNAs) are revealed to participate in the pathogenesis of CRC. This study aims to reveal the mechanism of hsa_circ_0000231 in Sev-mediated CRC progression. Methods The expression of hsa_circ_0000231 and microRNA-622 (miR-622) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein level was determined by western blot analysis. Cell proliferation was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell colony formation and DNA content quantitation assays. Cell apoptosis was detected by Annexin V-fluorescein isothiocyanate and propidium iodide double staining and caspase 3 activity assays. Cell migration and invasion were investigated by wound-healing and transwell invasion assays, respectively. The putative relationship between hsa_circ_0000231 and miR-622 was predicted by circular RNA Interactome online database, and identified by dual-luciferase reporter and RNA immunoprecipitation assays. The impacts of hsa_circ_0000231 on Sev-mediated tumor formation in vivo were presented by in vivo assay. Results Hsa_circ_0000231 expression was upregulated, while miR-622 was downregulated in CRC tissues and cells compared with control groups. Sev treatment decreased hsa_circ_0000231 expression, but increased miR-622 expression in CRC cells. Sev treatment suppressed cell proliferation, migration and invasion, and induced cell apoptosis. Hsa_circ_0000231 overexpression restored Sev-mediated CRC progression in vitro. Additionally, hsa_circ_0000231 acted as a sponge of miR-622, and miR-622 inhibitors reversed the impacts of hsa_circ_0000231 silencing on CRC process. Furthermore, Sev treatment inhibited tumor growth by regulating hsa_circ_0000231 in vivo. Conclusion Hsa_circ_0000231 attenuated Sev-aroused repression impacts on CRC development by sponging miR-622. This findings may provide an appropriate anesthetic protocol for CRC sufferers undergoing surgery.

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Atypical role of sprouty in p21 dependent inhibition of cell proliferation in colorectal cancer

Molecular Carcinogenesis ◽

10.1002/mc.22379 ◽

2015 ◽

Vol 55 (9) ◽

pp. 1355-1368 ◽

Cited By ~ 3

Author(s):

Qiong Zhang ◽

Katherine Shim ◽

Kevin Wright ◽

Alexander Jurkevich ◽

Sharad Khare

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Dependent Inhibition

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Dietary micronutrient intake and atherosclerosis in systemic lupus erythematosus

Lupus ◽

10.1177/0961203316655211 ◽

2016 ◽

Vol 25 (14) ◽

pp. 1602-1609 ◽

Cited By ~ 4

Author(s):

C Lourdudoss ◽

A-C Elkan ◽

I Hafström ◽

T Jogestrand ◽

T Gustafsson ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Atherosclerotic Plaque ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Systemic Lupus ◽

Micronutrient Intake ◽

And Gender ◽

Activity Measure

Objective The aim of this study was to investigate the role of dietary micronutrient intake in systemic lupus erythematosus (SLE). Methods This study included 111 SLE patients and 118 age and gender-matched controls. Data on diet (food frequency questionnaires) were linked with data on Systemic Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and carotid atherosclerotic/echolucent plaque (B-mode ultrasound). Dietary micronutrient intake were compared between SLE patients and controls and in relation to lupus activity and atherosclerosis in SLE. Associations between micronutrient intake and plaque were analyzed through logistic regression, adjusted for potential confounders. Results Micronutrient intake did not differ between patients and controls, and between lower and higher lupus activity, apart from the fact that phosphorus was associated with SLEDAI > 6. In SLE patients, some micronutrients were associated with atherosclerotic plaque, left side. Lower intake of riboflavin and phosphorus was associated with atherosclerotic plaque, left side (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.12–8.40 and OR 4.36, 95% CI 1.53–12.39, respectively). Higher intake of selenium and thiamin was inversely associated with atherosclerotic plaque, left side (OR 0.28, 95% CI 0.09–0.89 and OR 0.26, 95% CI 0.08–0.80, respectively). In addition, higher intake of thiamin was inversely associated with echolucent plaque, left side (OR 0.22, 95% CI 0.06–0.84). Lower intake of folate was inversely associated with bilateral echolucent plaque (OR 0.36, 95% CI 0.13–0.99). Conclusions SLE patients did not have different dietary micronutrient intake compared to controls. Phosphorus was associated with lupus activity. Riboflavin, phosphorus, selenium and thiamin were inversely associated with atherosclerotic plaque, left side in SLE patients, but not in controls. Dietary micronutrients may play a role in atherosclerosis in SLE.

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Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity

AJP Renal Physiology ◽

10.1152/ajprenal.00261.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. F262-F270 ◽

Cited By ~ 11

Author(s):

Hae-Seong Yoon ◽

Terrence J. Monks ◽

Jeffrey I. Everitt ◽

Cheryl L. Walker ◽

Serrine S. Lau

Keyword(s):

Cell Proliferation ◽

Tissue Injury ◽

Tumor Development ◽

Suppressor Gene ◽

Tumor Formation ◽

Renal Tumors ◽

Outer Stripe ◽

Acute Tissue Injury ◽

Cell Cycle Deregulation ◽

Erk Activity

Although 2,3,5-tris-(glutathion- S-yl)hydroquinone (TGHQ; 2.5 μmol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type ( Tsc2+/+ ) and mutant Eker rats ( Tsc2 EK/+), only TGHQ-treated Tsc2 EK/+ rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2 EK/+ rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

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Free Fatty acids receptors (FFAR2 and FFAR3) control cell proliferation by regulating cellular glucose uptake

10.21203/rs.2.12250/v1 ◽

2019 ◽

Author(s):

Mohammad Aziz ◽

Saeed Al Mahri ◽

Amal Alghamdi ◽

Maaged AlAkiel ◽

Monira Al Aujan ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

Cell Proliferation ◽

Fatty Acid ◽

Free Fatty Acid ◽

Free Fatty Acids ◽

Glucose Uptake ◽

Microarray Data ◽

Free Fatty Acid Receptors

Abstract Background Colorectal cancer is a worldwide problem which has been associated with changes in diet and lifestyle pattern. As a result of colonic fermentation of dietary fibres, short chain free fatty acids are generated which activate Free Fatty Acid Receptors 2 and 3 (FFAR2 and FFAR3). FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells. Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis. Methods Transcriptome analysis console was used to analyse microarray data from patients and cell lines. We employed shRNA mediated down regulation of FFAR2 and FFAR3 genes which was assessed using qRT-PCR. Assays for glucose uptake and cAMP generation was done along with immunofluorescence studies. For measuring cell proliferation, we employed real time electrical impedance based assay available from xCelligence. Results Microarray data analysis of colorectal cancer patient samples showed a significant down regulation of FFAR2 gene expression. This prompted us to study the FFAR2 in colorectal cancer. Since, FFAR3 shares significant structural and functional homology with FFAR2, we knocked down both these receptors in colorectal cancer cell line HCT 116. These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of GLUT1. Since, FFAR2 and FFAR3 signal through G protein subunit (Gαi), knockdown of these receptors was associated with increased cAMP. Inhibition of PKA did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway. Conclusion: Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of protein kinase A mediated cAMP signalling. Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes. This study paves the way to understand the mechanism of action of short chain free fatty acid receptors in colorectal cancer.

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