Genetic variants of SMAD2/3/4/7 are associated with susceptibility to ulcerative colitis in a Japanese genetic background

Yamashita, Arisa; Inamine, Tatsuo; Suzuki, Shota; Fukuda, Saburo; Unoike, Miki; Kawafuchi, Yuka; Machida, Haruhisa; Isomoto, Hajime; Nakao, Kazuwa; Tsukamoto, Kazuhiro

doi:10.1016/j.imlet.2019.01.007

Cited by 14 publications

(7 citation statements)

References 33 publications

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“…However, Smad7 can inhibit BMP/TGF-βs signaling in multiple ways [36] [37]. In addition, Smad7 blocks Smads signaling by inhibiting the phosphorylation of Smad2/3 [38]. Once Smad7 is degraded via the ubiquitin proteasome degradation mechanism, Smad2/3 is activated [39].…”

Section: Discussionmentioning

confidence: 99%

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

Zhou

Huang

Zhao

et al. 2019

Aging

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Triple-negative breast cancer (TNBC) cannot be treated with current hormonal therapies and has a higher risk of relapse than other breast cancers. To identify potential therapeutic targets for TNBC, we conducted microRNA sequencing (RNA-Seq) in human TNBC specimens and tumor-matched controls. We found that growth differentiation factor-10 (GDF10), a member of the TGF-β superfamily, was downregulated in tumor samples. Further analysis of GDF10 expression in a larger set of clinical TNBC samples using qPCR confirmed its downregulation and association with parameters of disease severity. Using human-derived TNBC cell lines, we carried out GDF10 under- and overexpression experiments, which showed that GDF10 loss promoted cell proliferation and invasion. By contrast, overexpression of GDF10 inhibited proliferation, invasion, and epithelial mesenchymal transition (EMT) via upregulation of Smad7 and E-Cadherin, downregulation of p-Smad2 and N-Cadherin, and reduction of nuclear Smad4 expression. In addition, overexpression of GDF10 reduced tumor burden and induced apoptosis in a TNBC xenograft mouse model. These findings indicate that GDF10 acts as a tumor suppressor in mammary epithelial cells that limits proliferation and suppresses EMT. Efforts aimed at restoring GDF10 expression may thus bring a long-sought therapeutic alternative in the treatment of patients with TNBC.

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Section: Discussionmentioning

confidence: 99%

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

Zhou

Huang

Zhao

et al. 2019

Aging

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“…Additionally, it has been reported that Wnt5a can promote interferon- γ signaling, leading to IL-12 expression in dendritic cells, thereby inducing Th1 differentiation in colitis [ 23 ]. It is speculated that genetic variants of SMAD2/3/4/7 might alter the balance of differentiation between Th17 and T, resulting in the development of inflammatory bowel disease, including ulcerative colitis [ 24 ]. Smad3-dependent disruption of the TGF- β signaling pathway has been shown to impair the healing of murine intestinal mucosal ulcers [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Small RNA Sequencing Reveals Differentially Expressed miRNAs in Necrotizing Enterocolitis in Rats

Wang

Jiang

et al. 2020

BioMed Research International

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Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal disease in preterm infants. The role of miRNAs in NEC is still unknown. The objective of this study was to identify differentially expressed (DE) miRNAs in rats with NEC and analyze their possible roles. In this study, a NEC rat model was established using Sprague-Dawley rat pups. Small RNA sequencing was used to analyze the miRNA expression profiles in the NEC and control rats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to identify target mRNAs for the DE miRNAs and to explore their potential roles. The DE miRNAs were verified by real-time quantitative PCR (RT-qPCR). The status of intestinal injury and the elevated levels of inflammatory cytokines in the NEC group confirmed that the NEC model was successfully established. The 16 miRNAs were found to be differentially expressed between the NEC group and the control group of rats. Bioinformatics analysis indicated that the parental genes of the DE miRNAs were predominantly implicated in the phosphorylation, cell migration, and protein phosphorylation processes. Moreover, the DE miRNAs were mainly found to be involved in the pathways of axon guidance, endocytosis, and focal adhesion, as well as in the Wnt signaling pathway, which is related to colitis. The expression patterns of the candidate miRNAs (rno-miR-27a-5p and rno-miR-187-3p), as assessed by RT-qPCR, were in accordance with the expression patterns obtained by miRNA-sequencing. The miRNA/mRNA/pathway network revealed that rno-miR-27a-5p and rno-miR-187-3p might be involved in NEC via the Wnt signaling pathway. We found an altered miRNA expression pattern in rats with NEC. We hypothesize that rno-miR-27a-5p and rno-miR-187-3p might mediate the NEC pathophysiological processes via the Wnt signaling pathway.

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“…20,21 In addition, single nucleotide polymorphisms found in the SMAD3 gene in humans have been associated with increased recurring surgery risk in CD patients 22 and with increased risk of UC. 23 Thus, we rederived Smad3 -/mice GF to determine whether microbiomes associated with IBD directly contribute to disease development. GF Smad3 -/mice were extremely susceptible to intestinal inflammation upon fecal transfer from SPF Smad3 -/mice with IBD, resulting in severe inflammation throughout the cecum and colon very early after colonization.…”

Section: Discussionmentioning

confidence: 99%

Validation studies for germ-freeSmad3^-/-mice as a bio-assay to test the causative role of fecal microbiomes in IBD

et al. 2019

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While the association between microbiomes and inflammatory bowel disease (IBD) is well known, establishing causal relationships between the two is difficult in humans. Germ-free (GF) mice genetically susceptible to IBD can address this question. Smad3 -/mice with defective transforming growth factor ß signaling are a model of IBD and colon cancer. They develop IBD upon colonization with Helicobacter under specific pathogen-free conditions, suggesting a role of the microbiome in IBD in this model. Thus, we rederived Smad3 -/mice GF to determine the potential of using these mice for testing the causative role of microbiomes in IBD. We found that fecal microbiomes from mice with IBD cause more severe gut inflammation in GF Smad3 -/and wild type mice compared to microbiomes from healthy mice and that Helicobacter induces gut inflammation within the context of other microbiomes but not by itself. Unexpectedly, GF Smad3 +/+ and Smad3 +/mice given IBD microbiomes develop IBD despite their lack of disease in SPF conditions upon Helicobacter infection. This was not unique to the background strain of our Smad3 model ( 129); both wild type C57BL/6 and 129 strains developed IBD upon fecal transfer. However, wild type Swiss Webster stock was not susceptible, indicating that the genetic background of recipient mice influences the severity of IBD following fecal transfer. Our data suggest that the microbiome is an independent risk factor contributing to IBD development, and careful characterization of new GF models is needed to understand potential sources of confounding factors influencing microbiome studies in these mice.

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Genetic variants of SMAD2/3/4/7 are associated with susceptibility to ulcerative colitis in a Japanese genetic background

Cited by 14 publications

References 33 publications

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

Small RNA Sequencing Reveals Differentially Expressed miRNAs in Necrotizing Enterocolitis in Rats

Validation studies for germ-freeSmad3^-/-mice as a bio-assay to test the causative role of fecal microbiomes in IBD

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Genetic variants of SMAD2/3/4/7 are associated with susceptibility to ulcerative colitis in a Japanese genetic background

Cited by 14 publications

References 33 publications

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

Small RNA Sequencing Reveals Differentially Expressed miRNAs in Necrotizing Enterocolitis in Rats

Validation studies for germ-freeSmad3-/-mice as a bio-assay to test the causative role of fecal microbiomes in IBD

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Validation studies for germ-freeSmad3^-/-mice as a bio-assay to test the causative role of fecal microbiomes in IBD