Identification of a Novel Substance P–Neurokinin-1 Receptor MicroRNA-221-5p Inflammatory Network in Human Colonic Epithelial Cells

Fang, Kai; Sideri, Aristea; Law, Ivy Ka Man; Bakirtzi, Kyriaki; Polytarchou, Christos; Iliopoulos, Dimitrios; Pothoulakis, Charalabos

doi:10.1016/j.jcmgh.2015.06.008

Cited by 23 publications

(30 citation statements)

References 54 publications

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“…Recent reports underscore the need for deciphering the complex interactions involving mediators and specialized cell types that maintain human intestinal homeostasis 16, 22, 23, 24, 25, 26. The current study aimed to decipher the mechanisms of IFN alpha action on the human adult normal mucosa homeostasis, in ex vivo explant cultures, an integrated model system maintaining the 3D architecture of the mucosa, which allows us to highlight potential cellular cross-talk between mucosal resident cells through diverse cytokines 15, 16.…”

Section: Discussionmentioning

confidence: 99%

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

Jarry

Malard

Bou-Hanna

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Backgound & AimsSeveral lines of investigation suggest that interferon (IFN) alpha can alter human intestinal mucosa homeostasis. These include the endogenous production of IFN alpha in celiac disease or inflammatory bowel diseases, as well as the occurrence of intestinal side effects of exogenous IFN alpha used as a therapeutic tool. Here, we present an ex vivo translational approach to investigate the effects of IFN alpha on the human normal intestinal mucosa, as well as its underlying mechanisms.MethodsHuman normal colonic mucosa explants were cultured in the presence or absence of IFN alpha 2a. Epithelial homeostasis was assessed using the immunohistochemical marker of apoptosis M30. The Wnt inhibitor Dickkopf-Homolog-1 (DKK1) was assayed in the supernatants by enzyme-linked immunosorbent assay. Activation of the inflammasome (caspase-1/interleukin [IL]18) and of a Th1 response was determined by in situ detection of active caspase-1, as well as by measurement of mature IL18 production and the prototype Th1 cytokine IFN gamma by enzyme-linked immunosorbent assay. In addition, mechanistic studies were performed using the specific caspase-1 inhibitor Tyr-Val-Ala-Asp(OMe)-fluoromethylketone (YVAD-FMK), IL18-binding protein, neutralizing anti–IFN gamma, and anti-DKK1 antibodies.ResultsIFN alpha 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN gamma response elicited by resident T box expressed in T cells–positive lamina propria cells. Both apoptosis and Th1 response were subordinated to active caspase-1 and IL18 production. Finally, neutralization of IFN gamma–induced DKK1 partially protected against IFN alpha–induced epithelial apoptosis.ConclusionsBy using an ex vivo model, we show an interindividual heterogeneity of IFN alpha effects. We show that IFN alpha is able to disrupt both epithelial and immune homeostasis in the human intestine, by activation of an innate immunity platform, the inflammasome, which drives a Th1 response and leads to epithelial barrier disruption.

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Section: Discussionmentioning

confidence: 99%

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

Jarry

Malard

Bou-Hanna

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…Apart from the aforementioned cell lines, miR-221 has also been studied in colonic epithelial cells with similar results. Fang et al[ 49 ] have shown that down regulation of miR-221 leads to amplification of experimental colitis and increase of TNFα in histological specimens. All the above highlight a plausible role of miR-221 in inflammatory response either through ICAM regulation, a molecule suggested to interfere with IBD inflammation facilitation[ 34 , 50 , 51 ], either through still unraveled mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Association of miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172 polymorphisms with anti-TNF treatment response in a Greek population with Crohn’s disease

Papaconstantinou

Kapizioni

Legaki

et al. 2017

WJGPT

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AIMTo investigate the correlation between rs2910164, rs11 614913, rs113054794, and rs188519172 polymorphisms and response to anti-TNF treatment in patients with Crohn’s disease (CD).METHODSOne hundred seven patients with CD based on standard clinical, endoscopic, radiological, and pathological criteria were included in the study. They all received infliximab or adalimumab intravenously or subcutaneously at standard induction doses as per international guidelines. Clinical and biochemical response was assessed using the Harvey-Bradshaw index and CRP levels respectively. Endoscopic response was evaluated by ileocolonoscopy at week 12-20 of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Whole peripheral blood was extracted and genotyping was performed by PCR.RESULTSOne hundred and seven patients were included in the study. Seventy two (67.3%) patients were classified as complete responders, 22 (20.5%) as partial while 13 (12.1%) were primary non-responders. No correlation was detected between response to anti-TNF agents and patients’ characteristics such as gender, age and disease duration while clinical and biochemical indexes used were associated with endoscopic response. Concerning prevalence of rs2910164, rs11614913, and rs188519172 polymorphisms of miR-146, miR-196a and miR-224 respectively no statistically important difference was found between complete, partial, and non-responders to anti-TNF treatment. Actually CC genotype of rs2910164 was not detected in any patient. Regarding rs113054794 of miR-221, normal CC genotype was the only one detected in all studied patients, suggesting this polymorphism is highly rare in the studied population.CONCLUSIONNo correlation is detected between studied polymorphisms and patients’ response to anti-TNF treatment. Polymorphism rs113054794 is not detected in our population.

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“…In present study, we demonstrated that SP promotes the development of gastric cancer by increasing cell viability and suppressing apoptosis in gastric cancer cells, which is consistent with previous studies. Furthermore, there is evidence that miR-877-5p expression could be regulated by SP in the development of cancer [22]. Here, we further explored the relationship between miR-877-5p and SP in the development of gastric cancer.…”

Section: -1-ig)mentioning

confidence: 99%

“…In addition, studies have found that some miRNAs in cancer cells were regulated by SP. Specifically, SP could down-regulate the expression of miR-877-5p in human colon epithelial cells [22]. However, whether SP regulates the expression of miR-877 in gastric cancer cells remains unclear.…”

mentioning

confidence: 99%

miR-877-5p antagonizes the promoting effect of SP on the gastric cancer progression

Guo¹,

Zhang²,

Sha³

2021

neo

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Gastric cancer is one of the four major tumors in the world and the second leading cause of cancer-related death. It was reported that Substance P (SP), as an oncogenic factor, could regulate the expression of miRNAs in gastric cancer progression. Here, we focused on the role of miR-877-5p in gastric cancer development and the miR-877-5p involvement in the SP-mediated gastric cancer development. The mRNA expression level and cell proliferation were assessed by quantitative real-time PCR and cell counting kit-8 assay, respectively. Flow cytometry was conducted to detect apoptosis, followed by assessing the expression of related apoptosis factors. Dual-luciferase reporter assay was performed to validate the interaction between miR-877-5p and Forkhead cassette M1 (FOXM1). Our results showed that SP treatment significantly increased cell proliferation in gastric cancer. Moreover, the miR-877-5p expression was dose-dependently decreased by SP, whereas FOXM1 expression was markedly increased by SP in gastric cancer cells. miR-877-5p negatively regulated gastric cancer development via inhibiting cell p roliferation and promoting apoptosis accompanied by increased cleaved caspase-3, cleaved caspase-9, and bax protein levels and decreased bcl-2 level. We confirmed that miR-877-5p could target FOXM1 and negatively regulate its expression. Furthermore, we demonstrated that SP could promote cell proliferation and inhibit apoptosis, while miR-877-5p overexpression reversed the effect of SP on cell proliferation and apoptosis. These results suggest that miR-877-5p overexpression can antagonize the promoting effect of SP on the development of gastric cancer, indicating that miR-877-5p may serve as a promising therapeutic target for gastric cancer.

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Identification of a Novel Substance P–Neurokinin-1 Receptor MicroRNA-221-5p Inflammatory Network in Human Colonic Epithelial Cells

Cited by 23 publications

References 54 publications

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

Association of miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172 polymorphisms with anti-TNF treatment response in a Greek population with Crohn’s disease

miR-877-5p antagonizes the promoting effect of SP on the gastric cancer progression

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