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

Li, Jun; Yin, Jing; Shen, Wenzhi; Gao, Ruifang; Liu, Yanhua; Chen, Yanan; Li, Xiru; Liu, Chenghu; Xiang, Rong; Luo, Na

doi:10.1002/ar.23590

Cited by 56 publications

(54 citation statements)

References 37 publications

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“…We then investigated hypothetical miR-216a targets involved in the stemness phenotype. We used Target Scan Human as a bioinformatics tool for miRNA target prediction, focusing on a putative target, TLR4, which plays a significant role in breast cancer progression and metastasis [25,29] and that has also been reported to be a direct target of miR-216a-5p in renal carcinoma [30]. We found that TLR4 expression was higher in MDA-MB-231 and T47D stem cells compared to differentiated cells at both protein and mRNA levels ( Figure 4A,B).…”

Section: Mirna-216a Targets Tlr4mentioning

confidence: 99%

miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

Roscigno

Cirella

Affinito

et al. 2020

IJMS

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Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

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Section: Mirna-216a Targets Tlr4mentioning

confidence: 99%

miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

Roscigno

Cirella

Affinito

et al. 2020

IJMS

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“…It is well established that tumorigenesis is a multi-step process caused by various factors, such as environmental carcinogens, in ammatory mediators, and tumor promoters. Multiple effects had been identi ed of TLR4 in tumor progression [11,[25][26][27][28]. In breast cancer cells and primary breast cancer tissues from patients, TLR4 expression was found to be up-regulated both at mRNA and protein levels, and signi cantly correlated with the high incidence of lymph node metastasis [11,26].…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer cells and primary breast cancer tissues from patients, TLR4 expression was found to be up-regulated both at mRNA and protein levels, and signi cantly correlated with the high incidence of lymph node metastasis [11,26]. Moreover, as TLRs ligands, LPS was reported to increase breast cancer metastasis in vitro and in vivo [27], and acquiring of high metastatic potential upon the TLR4-elicited activation of NF-κB in breast cancer cells was associated with integrin αvβ3, TPM1 and maspin [28]. However, Connelly et al suggested that inhibition of NF-κB might lead to the increased tumor latency and decreased tumor burden and numbers of lung metastases during breast cancer development in mice [29].…”

Section: Discussionmentioning

confidence: 99%

Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Long

Lin

Zhang

et al. 2020

Preprint

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Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide I (AT-I) is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear.Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray (TMA) and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea (NMU) induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments.Results：We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit NMU-induced rat mammary tumor progression through TLR4/NF-κB pathway.Conclusions: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.

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“…The esophagus, a hollow viscera, is frequently stimulated by LPS along with eating behavior. LPS has been reported to promote the proliferation and migration of various tumors including ESCC [6][7][8]. However, no study has investigated whether LPS could regulate the stemness of ESCC.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma

Liu

et al. 2020

Cell Commun Signal

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Background: Esophageal squamous cell cancer (ESCC) is one kind of frequent digestive tumor. The inflammatory environment plays an important role in the tumorigenesis and development of ESCC. Cancer stem cells are a small group of tumor cells with stem cell characteristics, which can potentially hinder the tumor management and treatment. Methods: ELISA was performed to detect the lipopolysaccharide concentration in cancer tissues. qPCR, Western blot, FACS, Immunohistochemistry, Immunofluorescence and Dot blot were applied to detect target genes expression. CCK-8, Colony-formation, Transwell, Sphere and Xenograft were conducted to investigate the function of cells, influenced by risk factors. The survival curve was drawn with the Kaplan-Meier product limit estimator. Nano-hmC-Seal-seq was utilized to detect the downstream target of TET3. ChIP-qPCR was adopted to demonstrate the transcriptional regulation of stem cell-associated genes by HOXB2. Results: Lipopolysaccharide concentration was significantly up-regulated in ESCC. High concentration of lipopolysaccharide stimulation induced the stemness of ESCC cells. TET3 expression was elevated with lipopolysaccharide stimulation via p38/ERK-MAPK pathway in ESCC and negatively correlated with patients' survival. TET3 induced the stemness of ESCC cells. Nano-hmC-Seal-seq showed that TET3 overexpression led to a significant increase in 5hmC levels of HOXB2 gene region, which was thus identified as the downstream target of TET3. The binding of HOXB2 to NANOG and cMYC was verified by ChIP-qPCR. Conclusions: Lipopolysaccharide served as a tumor promotor in ESCC by inducing cancer cell stemness through the activation of a LPS-TET3-HOXB2 signaling axis, which might provide a novel therapeutic strategy for ESCC.

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

Cited by 56 publications

References 37 publications

miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma

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