Multiple Roles of Toll-Like Receptor 4 in Colorectal Cancer

Yesudhas, Dhanusha; Gosu, Vijayakumar; Anwar, Muhammad Ayaz; Choi, Sangdun

doi:10.3389/fimmu.2014.00334

Cited by 90 publications

(69 citation statements)

References 126 publications

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“…Our study further substantiates and extends our knowledge concerning the role of TLR4 in previous studies involving both intestinal and breast tumors (Santaolalla et al, ; Yang et al, ; Yesudhas et al, ). TLRs defend against invading microorganisms by recognizing various motifs of microbial origin called pathogen‐associated molecular patterns (PAMPs) (Janeway and Medzhitov, ; Akira et al, ).…”

Section: Discussionsupporting

confidence: 92%

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Yin

Shen

et al. 2017

The Anatomical Record

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Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 300:1219-1229, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 92%

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Yin

Shen

et al. 2017

The Anatomical Record

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“…In addition, KO mice exhibited higher levels of other Gram negative bacteria that are able to stimulate TLR4 and increase its expression, such as Clostridium (Scarpa et al, 2011), B. vulgates (Haller et al, 2004), Acinetobacter (Erridge et al, 2007), or Pseudomonadaceae (Korneev et al, 2015). Today it is widely accepted that in normal intestinal epithelial cells, TLR4 is marginally expressed but under pathological conditions such as IBD and CRC an overexpression of this receptor occurs (Yesudhas et al, 2014). However, it has not been well established whether this TLR4 elevation occurs prior to IBD breakout or is a consequence of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…In normal gut, intestinal epithelial cells maintain a beneficial link with the microorganisms in the intestinal flora through toll-like receptors (TLRs), which mediate signaling to maintain epithelial cell integrity and tight junctions (Yesudhas et al, 2014). Stimulation from commensal bacteria is finite and should not trigger an excessive inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

“…However, any alteration in the population of luminal bacteria may influence TLR signaling, paving the way to a dysregulated inflammatory response, thus being a common denominator of IBD and CRC (Ha et al, 2014). Altered expression patterns of TLRs lead to tumor development, and in this context the contribution of TLR4 is considerably higher than those of other TLRs (Yesudhas et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

et al. 2016

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The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in the drinking water. Colitis was evaluated using a clinical symptoms index, histopathological analyses, and qRT-PCR. Abrogation of the adm gene in the whole body was confirmed by PCR and qRT-PCR. KO mice exhibit significant changes in colonic microbiota: higher proportion of δ-Proteobacteria class; of Coriobacteriales order; and of other families and genera was observed in KO feces. Meanwhile these mice had a lower proportion of beneficial bacteria, such as Lactobacillus gasseri and Bifidobacterium choerinum. TLR4 gene expression was higher (p < 0.05) in KO animals. AM deficient mice treated with DSS exhibited a significantly worse colitis with profound weight loss, severe diarrhea, rectal bleeding, colonic inflammation, edema, infiltration, crypt destruction, and higher levels of pro-inflammatory cytokines. No changes were observed in the expression levels of adhesion molecules. In conclusion, we have shown that lack of AM leads to changes in gut microbiota population and in a worsening of colitis conditions, suggesting that endogenous AM is a protective mediator in this pathology.

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“…Herszenyi et al (2014) proved that proteolytic enzymes play an important role in CRC metastasis. Yesudhas et al (2014) reported that TLR-4 was a critical target in CRC metastasis. In this study, we focused on exploring the potential cause of CRC metastasis and on screening molecular targets by the analysis of gene and miRNA expression profiles from microarray data.…”

Section: Introductionmentioning

confidence: 99%

Identification of critical TF-miRNA-mRNA regulation loops for colorectal cancer metastasis

Wang

Liu

2015

Genet. Mol. Res.

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ABSTRACT. To explore the potential cause of colorectal cancer metastasis, gene expression profiles, GSE21510, and miRNA expression profiles, GSE48074, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes in metastatic colorectal and non metastatic colorectal cancer compared with the normal samples were identified via the limma package in R. The differentially expressed miRNAs in colorectal cancer samples with lymph node metastasis compared with those without lymph node metastasis were screened out by the some method. Differentially expressed genes that were upregulated in colorectal cancer samples with distant metastasis in comparison to that in samples without distant metastasis and normal samples were considered to play important roles in colorectal cancer metastasis. Functional enrichment analysis of these genes was conducted using the Database for Annotation, Visualization, and Integrated Discovery v6.7. Biological processes related to cell differentiation and cell proliferation were significantly enriched. TF (transcription factor)-miRNA-mRNA regulation loops were constructed by using the starBase and ChIPBase databases. Finally, six critical regulation loops were screened out. They were composed of two C. Wang et al. 5486©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 5485-5495 (2015) TFs, two miRNAs, and three mRNAs. Some of these TFs, mRNAs, or miRNAs have previously been identified as critical targets in colorectal cancer metastasis. Additionally, several new targets were identified in our study, which may be helpful to improve metastatic colorectal cancer treatment.

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Multiple Roles of Toll-Like Receptor 4 in Colorectal Cancer

Cited by 90 publications

References 126 publications

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

Identification of critical TF-miRNA-mRNA regulation loops for colorectal cancer metastasis

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