Enhanced expression of proproliferative and antiapoptotic genes in ulcerative colitis-associated neoplasia

Švec, Jiří; Musı́lková, Jana; Bryndová, Jana; Jirásek, Tomáš; Mandys, Václav; Kment, Milan; Pácha, Jiřı́

doi:10.1002/ibd.21178

Cited by 12 publications

(6 citation statements)

References 34 publications

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“…These proteins are involved in cell cycle regulation, proliferation, and apoptosis. As there is increased cell turnover in UC associated with neoplastic transformation and transfection of miR-143 and miR-145 inhibits proliferation in transfected cells, these cell cycle and cell death regulators were of interest to study in high-risk individuals (11, 23, 30–32, 42). This is the first study in ulcerative colitis to determine expression levels of these proteins that have potential roles in inflammation-associated neoplastic transformation.…”

Section: Discussionmentioning

confidence: 99%

“…With chronic inflammation, the epithelium undergoes recurrent injury and healing that is thought to predispose to the risk of malignant transformation (6, 7). Molecular and genetic changes accompany this transformation and may occur before there is histological evidence of dysplasia (6, 8–11). In this regard, several previous studies have reported differences in colonic mucosal gene expression in IBD patients compared to normal controls (12–15).…”

Section: Introductionmentioning

confidence: 99%

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miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

Pekow

Dougherty

Mustafi

et al. 2012

Inflammatory Bowel Diseases

108

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Background miR-143 and miR-145 are believed to function as colon cancer tumor suppressors as they inhibit colon cancer cell growth and are down-regulated in sporadic colonic tumors. We speculated that miR-143 and miR-145 might also be down-regulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). Methods Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR-143 and miR-145 were quantified by real time PCR and miR-145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K-RAS, API5, MEK-2 (miR-143), and IRS-1 (miR-145) were determined by Western blotting. To assess the effects of miR-143 and miR-145 on these predicted targets, HCT116 and HCA-7 colorectal cancer cells were transfected with miR-143 and miR-145 and expression levels of these proteins were measured. Results In UC, miR-143 and miR-145 were significantly down-regulated 8.3-fold (3.4–20.1) (p < 0.0001) and 4.3-fold (2.3–7.8) (p < 0.0001), respectively, compared to normal colon. In contrast, IRS-1, K-RAS, API5, and MEK-2 were up-regulated in ulcerative colitis consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR-143 and miR-145 significantly down-regulated these proteins in HCT116 or HCA7 cells. Conclusion Compared to normal colonic mucosa, in chronic ulcerative colitis miR-143 and miR-145 were significantly down-regulated and their predicted targets, IRS-1, K-RAS, API5, and MEK-2 were up-regulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

Pekow

Dougherty

Mustafi

et al. 2012

Inflammatory Bowel Diseases

108

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“…It is known that iNOS/nitric oxide plays an integral role during intestinal inflammation, and the expression of iNOS was significantly increased in inflamed colon [42,43]. However, whether iNOS is induced in the hindgut in HFD mediated obesity mice is still unclear.…”

Section: Accepted Manuscriptmentioning

confidence: 97%

Colonic inflammation accompanies an increase of β-catenin signaling and Lachnospiraceae/Streptococcaceae bacteria in the hind gut of high-fat diet-fed mice

Zeng

Ishaq

Zhao

et al. 2016

The Journal of Nutritional Biochemistry

145

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Consumption of an obesigenic/high-fat diet (HFD) is associated with a high colon cancer risk and may alter the gut microbiota. To test the hypothesis that long-term high-fat (HF) feeding accelerates inflammatory process and changes gut microbiome composition, C57BL/6 mice were fed HFD (45% energy) or a low-fat (LF) diet (10% energy) for 36 weeks. At the end of the study, body weights in the HF group were 35% greater than those in the LF group. These changes were associated with dramatic increases in body fat composition, inflammatory cell infiltration, inducible nitric oxide synthase protein concentration and cell proliferation marker (Ki67) in ileum and colon. Similarly, β-catenin expression was increased in colon (but not ileum). Consistent with gut inflammation phenotype, we also found that plasma leptin, interleukin 6 and tumor necrosis factor α concentrations were also elevated in mice fed the HFD, indicative of chronic inflammation. Fecal DNA was extracted and the V1-V3 hypervariable region of the microbial 16S rRNA gene was amplified using primers suitable for 454 pyrosequencing. Compared to the LF group, the HF group had high proportions of bacteria from the family Lachnospiraceae/Streptococcaceae, which is known to be involved in the development of metabolic disorders, diabetes and colon cancer. Taken together, our data demonstrate, for the first time, that long-term HF consumption not only increases inflammatory status but also accompanies an increase of colonic β-catenin signaling and Lachnospiraceae/Streptococcaceae bacteria in the hind gut of C57BL/6 mice.

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“…N-acetylcysteine inhibited chronic ulcerative colitis-associated colorectal adenocarcinoma development, possibly by reduction of nitrative DNA damage produced via iNOS in a murine model (Seril et al, 2002). Moreover, the expression of iNOS mRNA was significantly increased during neoplastic transformation of colonic mucosa in ulcerative colitis patients (Svec, et al, 2010). These data implicate that iNOS/NO plays a role in inflammation-associated carcinogenesis of the gut.…”

Section: Introductionmentioning

confidence: 72%

Demethoxycurcumin from Curcuma longa Rhizome Suppresses iNOS Induction in an in vitro Inflamed Human Intestinal Mucosa Model

Somchit

Changtam

Kimseng³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: It is known that inducible nitric oxide synthase (iNOS)/nitric oxide (NO) plays an integral role during intestinal inflammation, an important factor for colon cancer development. Natural compounds from Curcuma longa L. (Zingiberaceae) have long been a potential source of bioactive materials with various beneficial biological functions. Among them, a major active curcuminoid, demethoxycurcumin (DMC) has been shown to possess anti-inflammatory properties in lipopolysaccharide (LPS)-activated macrophages or microglia cells. However, the role of DMC on iNOS expression and NO production in an in vitro inflamed human intestinal mucosa model has not yet been elucidated. This study concerned inhibitory effects on iNOS expression and NO production of DMC in inflamed human intestinal Caco-2 cells. An in vitro model was generated and inhibitory effects on NO production of DMC at 65 μM for 24-96 h were assessed by monitoring nitrite levels. Expression of iNOS mRNA and protein was also investigated. DMC significantly decreased NO secretion by 35-41% in our inflamed cell model. Decrease in NO production by DMC was concomitant with down-regulation of iNOS at mRNA and protein levels compared to proinflammatory cytokine cocktail and LPS-treated controls. Mechanism of action of DMC may be partly due to its potent inhibition of the iNOS pathway. Our findings suggest that DMC may have potential as a therapeutic agent against inflammation-related diseases, especially in the gut.

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Enhanced expression of proproliferative and antiapoptotic genes in ulcerative colitis-associated neoplasia

Cited by 12 publications

References 34 publications

miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

Colonic inflammation accompanies an increase of β-catenin signaling and Lachnospiraceae/Streptococcaceae bacteria in the hind gut of high-fat diet-fed mice

Demethoxycurcumin from Curcuma longa Rhizome Suppresses iNOS Induction in an in vitro Inflamed Human Intestinal Mucosa Model

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