High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

Wang, El; Qian, Zhi Rong; Nakasono, Masahiko; Tanahashi, Takao; Yoshimoto, Katsuhiko; Bando, Yoshimi; Kudo, Eiji; Shimada, Mitsuo; Sendo, Toshiaki

doi:10.1038/sj.bjc.6605558

Cited by 215 publications

(186 citation statements)

References 40 publications

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“…Xu et al showed that nickel promotes the invasive potential of human lung cancer cells via TLR4/MyD88 signaling (27). Wang et al suggested that the high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer (28). In this study, the expression of Foxp3 increased after LPS stimulation in a concentrationdependent manner, and the expression of Foxp3 decreased after inhibition of the TLR4 signaling pathway.…”

Section: Discussionsupporting

confidence: 54%

Foxp3 expression in A549 cells is regulated by Toll-like receptorï¿½4 through nuclear factor-κB

Yang

2012

Mol Med Report

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Abstract. Foxp3 is a master regulator of the development and function of CD4 + CD25 + regulatory T cells (Tregs). Previous studies have reported that Foxp3 is also expressed in tumour cells and promotes tumour immune evasion. However, the regulation of the expression of Foxp3 in tumour cells remains unclear. Toll-like receptor 4 (TLR4), a member of the pattern recognition receptor family, is also expressed in tumour cells. Previous studies have found that the TLR4 signaling pathway is involved in tumour immune evasion in lung cancer cells, and that the transcription factor, nuclear factor-κB (NF-κB), plays a key role in the TLR4 signaling pathway. Moreover, recent studies found that NF-κB promotes the transcription of Foxp3. We hypothesised that TLR4 may also be involved in the regulation of Foxp3 in A549 cells through NF-κB. Therefore, we examined the effect of TLR4 and NF-κB on the expression of Foxp3 in the A549 lung cancer cell line. The results showed that Foxp3 and TLR4 are expressed in A549 cells; the expression of Foxp3 increased after lipopolysaccharide (LPS) stimulation and decreased after blocking the TLR4 signaling pathway. In addition, the expression of NF-κB (p65) increased after LPS stimulation and the expression of Foxp3 decreased after blocking NF-κB. These results suggest that TLR4 is involved in the regulation of Foxp3 in A549 cells through NF-κB.

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Section: Discussionsupporting

confidence: 54%

Foxp3 expression in A549 cells is regulated by Toll-like receptorï¿½4 through nuclear factor-κB

Yang

2012

Mol Med Report

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“…2B and C), for example, transcription factors activated upon immune activation. Given that high MYD88 levels correlate with poor colorectal cancer prognosis (26), future work outside the scope of this present study may be able to address whether rs4988453 modulates MyD88 or ACAA1 levels in primary cells and/or colorectal cancer tissue arrays.…”

Section: Discussionmentioning

confidence: 99%

Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival

et al. 2013

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Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n ¼ 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/ F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1b mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. Cancer Res; 73(24); 7232-42. Ó2013 AACR.

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“…The surface of the intestinal mucosa is constantly exposed to a large amount of bacterial lipopolysaccharide (LPS). Upregulated expression of the LPS receptor complex, CD14/Toll-like receptor (TLR4)/MD2, has been identified in the intestinal mucosa of animal models and patients with inflammatory bowel disease and colorectal cancers (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide

Kuo

Lee

2016

Cancer Research

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Colorectal carcinogenesis is affected by overexpression of the lipopolysaccharide (LPS) receptors CD14 and TLR4, which antagonize each other by affecting epithelial cell proliferation and apoptosis. Eritoran is an investigational drug for sepsis treatment that resembles the lipid A moiety of LPS and therefore acts as a TLR4 inhibitor. In the present study, we explored the potential therapeutic uses and mechanisms of action of eritoran in reducing colon cancer progression. Eritoran administration via intracolonic, intragastric, or intravenous routes significantly reduced tumor burden in a chemically induced mouse model of colorectal carcinoma. Decreased proliferation and increased apoptosis were observed in mouse tumor cells after eritoran treatment. In vitro cultures of mouse primary tumor spheroids and human cancer cell lines displayed increased cell proliferation and cell-cycle progression following LPS challenge. This effect was inhibited by eritoran and by silencing CD14 or TLR4. In contrast, apoptosis induced by eritoran was eliminated by silencing CD14 or protein kinase Cz (PKCz) but not TLR4. Lastly, LPS and eritoran caused hyperphosphorylation of PKCz in a CD14-dependent and TLR4-independent manner. Blocking PKCz activation by a Src kinase inhibitor and a PKCz-pseudosubstrate prevented eritoraninduced apoptosis. In summary, our work offers a preclinical proof of concept for the exploration of eritoran as a clinical treatment, with a mechanistic rationale to reposition this drug to improve the management of colorectal cancer.

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High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

Cited by 215 publications

References 40 publications

Foxp3 expression in A549 cells is regulated by Toll-like receptorï¿½4 through nuclear factor-κB

Foxp3 expression in A549 cells is regulated by Toll-like receptorï¿½4 through nuclear factor-κB

Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival

Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide

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