Effect of Estradiol in an Azoxymethane/Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development

Son, Hee Jin; Sohn, Sung Hwa; Kim, Nayoung; Lee, Ha Na; Lee, Sun Min; Nam, Ryoung Hee; Park, Ji Hyun; Song, Chin Hee; Shin, Eun Hee; Na, Hee Young; Kim, Sang Woo; Lee, Dong Hoon; Surh, Young Joon

doi:10.4143/crt.2018.060

Cited by 53 publications

(61 citation statements)

References 28 publications

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“…These changes are characterized by increased proinflammatory macrophages infiltration and epithelia permeability in the colon, which eventually can lead to insulin resistance (7). Estrogen treatment has been shown to elicit an anti-inflammatory response in the colon of mouse models for colitis (28,46). Our transcriptomic data revealed that while both sexes showed altered immune response upon HFD feeding, there were sex differences in the immune response.…”

Section: Discussionmentioning

confidence: 80%

“…Most of the CRC protective effect, however, has been linked to ERβ. Treatment with ERβ-selective agonist, for example, resulted in anti-inflammatory and anti-tumorigenic effects in different CRC mouse models (27)(28)(29)(30), and loss of ERβ results in pro-inflammatory environment and increased tumor development in both APC Min/+ and colitis-associated tumor mouse model (31,32)(Hases et al, under review). Notably, intestinal-specific deletion of ERβ strongly enhanced inflammatory signaling in the colon of both male and female mice (Hases et al, under review).…”

Section: Introductionmentioning

confidence: 99%

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High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Hases

Archer

Indukuri

et al. 2020

Preprint

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These authors contributed equally to the work. AbstractEpidemiological studies highlight a strong association between obesity and colorectal cancer (CRC), especially in men. Estrogen, on the other hand, is associated with protection against both the metabolic syndrome and CRC. The colon is the first organ to respond to a high-fat diet (HFD), and estrogen receptor beta (ERβ) in the intestine appears to prevent CRC. How estrogen impacts the colon under HFD condition has, however, not been investigated. Estrogen can act through three different receptors (ERα, ERβ, GPER1) which all may impact metabolism. In an effort to dissect this, we fed mice a control diet or a high-fat diet (HFD) for 13 weeks and administered receptor-selective estrogenic ligands for the last three weeks. We recorded corresponding physiological impact on fat distribution, fasting glucose, colon crypt proliferation and immune cell infiltration, and the colon transcriptome response. We identify clear sex-differences at the transcriptome level, both at base line and after HFD and ligand treatments. An unexpected observation was the significant sex-differences and impact by HFD and estrogens on circadian clock gene expression, such as Npas2 and Arntl (Bmal1), in the colon. Both sexes also exhibited an increased infiltration of F4/80+ macrophages as a result of HFD. In males, but not females, this was accompanied by changes in colonic epithelial cell proliferation. ERα-selective PPT treatment had significant systemic effects, reducing body weight in both sexes, whereas ERβ-selective DPN treatment did not impact body weight, but reduced infiltration of F4/80+ macrophages in colon of both sexes and attenuated HFD-induced proliferation of male colon crypts. Both ERα and ERβ activation contributed to circadian clock gene regulations. We detail for the first time how HFD and estrogens modulate the colon transcriptome and physiology in a sex and ER-specific manner.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Hases

Archer

Indukuri

et al. 2020

Preprint

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“…Most prominent are the corticosteroids, which are used to treat the acute relapse of inflammatory bowel disease (24, 25), and the macrolide antibiotics, which we have investigated further in this manuscript. Intriguingly the analysis also identified sex hormones such as medroxyprogesterone and estradiol which have been shown to modulate coli (26)tis, and colitis associated adnoma development in vivo (27); and non-steroidal anti-inflammatory drugs, which, in clinical practice, are identified as agents that exacerbate IBD (28). However, NSAIDs non-selectively inhibit cyclooxygenase (COX) activity resulting in inhibition of constitutively expressed COX-1 in the gastrointestinal epithelium, causing epithelial damage and ulceration; and inhibition of COX-2, which is upregulated at sites of inflammation.…”

Section: Discussionmentioning

confidence: 98%

“…Our list of drugs predicted to influence IBD outcomes included several drugs in routine use for IBD, most prominently the corticosteroids, which are used to treat acute relapses of inflammatory bowel disease 24 25 . The analysis also identified sex hormones including medroxyprogesterone and estradiol which have been shown to modulate colitis 26 , and colitis-associated adenoma development in vivo 27 ; and non-steroidal anti-inflammatory drugs, which, in clinical practice, are identified as agents that exacerbate IBD 28 . The harmful effects of NSAIDs result from inhibition of constitutively expressed COX-1 in the gastrointestinal epithelium, causing epithelial damage and ulceration; inhibition of COX-2, which is upregulated at sites of inflammation is a well-established anti-inflammatory mechanism, which influences NF-κB signalling.…”

Section: Discussionmentioning

confidence: 99%

Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease

Lloyd¹,

Παπουτσοπουλου

Smith

et al. 2019

Preprint

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ObjectiveInflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.DesignThe SysmedIBD consortium established a novel drug-repurposing pipeline based on a combination of in-silico drug discovery and biological assays targeted at demonstrating an impact on NF-kappaB signalling, and a murine model of IBD.ResultsThe drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic Clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions.Clarithromycin’s effects were validated in several experiments: it influenced NF-κB mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids.ConclusionsThese findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.

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“…Recently, neural-immune-endocrine network including nerve growth factors has attracted increasing attention not only in IBS, 11 but also in esophageal 20,23,24 and gastric pathophysiology. 25 In the esophagus, TRPV1 receptors and neurotropic factors have been reported to play an important role in the inflammatory process. 23,24 Our team has also demonstrated that TRPV1, GDNF, and NGF are up-regulated in reflux esophagitis.…”

Section: Discussionmentioning

confidence: 99%

Expression of Neurotrophic Factors, Tight Junction Proteins, and Cytokines According to the Irritable Bowel Syndrome Subtype and Sex

Lee

Kim

Park

et al. 2020

J Neurogastroenterol Motil

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Background/AimsEmerging evidence shows that the mechanism of irritable bowel syndrome (IBS) is associated with neurotrophic factors and tight junction proteins (TJPs). It is known that there are sex differences in the pathophysiology of IBS. The aim of the present study is to determine expression levels of neurotrophic factors, TJPs, and cytokines according to IBS subtype and sex. MethodsFrom 59 IBS (33 IBS-constipation, 21 IBS-diarrhea, and 5 IBS-mixed) and 36 control patients, colonic mucosa mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1), nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and various TJPs were assessed by real-time polymerase chain reaction. Western blot was performed to determine levels of zonular occludens-1 (ZO-1). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay. ResultsTRPV1, GDNF, and NGF mRNA levels were significantly increased in those with IBS-constipation compared to those in controls (all P < 0.05). However, they showed no significant difference between those with IBS-diarrhea and controls. Expression level of TRPV1 correlated with that of GDNF (r = 0.741, P < 0.001) and NGF (r = 0.935, P < 0.001). ZO-1 RNA expression levels were lower (P = 0.021) in female IBS-diarrhea than those in controls, although they showed no significant differences between male IBS-diarrhea and controls. Serum IL-1β levels in female IBS were significantly higher than those of male IBS, especially in IBS-constipation (P < 0.001). ConclusionOur results suggest that neurotrophic factors and IL-1β are closely related to IBS-constipation and that decrease of ZO-1 is an important factor in female with IBS-diarrhea. (J Neurogastroenterol Motil 2020;26:106-116)

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Effect of Estradiol in an Azoxymethane/Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development

Abstract: The data suggest that estradiol inhibits the initiation of CRC by regulating Nrf2-related pathways. Moreover, these imply the dual role of Nrf2 and NLRP3 inflammasome, including promotion of tumor progression upon tumor initiation.

Cited by 53 publications

References 28 publications

High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease

Expression of Neurotrophic Factors, Tight Junction Proteins, and Cytokines According to the Irritable Bowel Syndrome Subtype and Sex

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