<scp>TLR</scp>4 increases the stemness and is highly expressed in relapsed human hepatocellular carcinoma

Zhou, Shuang; Du, Renle; Li, Xiqing; Shen, Wenzhi; Gao, Ruifang; Jiang, Shan; Fang, Yan; Shi, Yuzhi; Chang, Antao; Liu, Lei; Liu, Chenghu; Li, Na; Xiang, Rong

doi:10.1002/cam4.2070

Cited by 24 publications

(13 citation statements)

References 41 publications

(85 reference statements)

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“…More and more evidences show that LPS plays a role in the development of HCC. Zhou et al 344 found that LPS activates the TLR4–AKT–SOX2 signaling pathway of liver cancer cell lines to improve the ability of cancer stem cells; Lin et al 345 found that there is a positive feedback loop of COX-2/PGE2/signal transducer and activator of transcription factor 3 (STAT3) activated by LPS in liver cancer cells, which regulates the expression of genes related to tumor proliferation, differentiation, and apoptosis. In the latest research on the treatment of liver cancer, it is found that the antitumor effect of TLR9 agonist combined with anti-PD-1 antibody or anti-PD-L1 is significantly better than single-agent therapy.…”

Section: Prr-related Diseasesmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

857

515

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Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

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Section: Prr-related Diseasesmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

857

515

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“… 10 Toll-like receptor 4 (TLR4)/Akt signalling was shown to promote cancer stemness in HCC cell lines, as reflected by an increase in the CD133 + CD49 + HCC cell population, by upregulating Sox2. 20 The enhanced tumorigenicity of CD133 + CD49 + HCC cells was also Nanog dependent, 21 as CD133 + Nanog high cells had increased expression of insulin-like growth factor 2 (IGF2) mRNA-binding protein-3 and YAP1, which ultimately inhibited transforming growth factor-β (TGF-β) signalling from suppressing TLR4 signalling. 21 …”

Section: Markers For Cancer Stemness In the Livermentioning

confidence: 99%

Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential

Tsui

Chan

2020

Br J Cancer

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Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment—both physical and cellular—is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.

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“…More importantly, Zhou et al proved that TLR4 expression was substantially upregulated in tumor tissues from HCC patients compared to adjacent tissues (Yao et al 2018 ). In addition, other research has demonstrated the promotive role for TLR4 in the development of HCC cells, and TLR4 inhibition was shown to have strong effects on LPS-induced inflammation and HCC cell proliferation (Lin et al 2016a ; Zhou et al 2019 ). Similar to these studies, the results in our studies suggested that RTF could significantly inhibit the expression of TLR4, as well as the activation of the NF-κB pathway, in HCC cells, which resulted in the suppression of various malignant behaviors of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Total flavonoids of Radix Tetrastigma suppress inflammation-related hepatocellular carcinoma cell metastasis

2021

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This study aimed to investigate the effects of the total flavonoids of Radix Tetrastigma (RTF) on inflammation-related hepatocellular carcinoma (HCC) development. Extracted RTF was diluted to different concentrations for subsequent experiments. HCC cells were cotreated with lipopolysaccharide (LPS) and RTF to investigate the effects of RTF on LPS-stimulated HCC cells. A CCK-8 kit was used to measure cell proliferation. Apoptosis was detected with a flow cytometer. Cell migration and invasion were quantified by wound healing and Transwell assays, respectively. The expression of TLR4 and COX-2 and activation of the NF-κB pathway were determined by Western blotting. Treatment with LPS significantly enhanced cell proliferation and decreased the apoptosis rate, while cell migration and invasion were notably upregulated. RTF suppressed the proliferation and invasion induced by LPS stimulation and promoted HCC cell apoptosis. The protein levels of Bax and cleaved caspase-3 were decreased and that of Bcl-2 was increased by LPS in HCC cells, which could be rescued by RTF. RTF significantly inhibited the LPS-induced expression of the proinflammatory mediators IL-6 and IL-8 in HCC cells. Mechanistically, with RTF treatment, the upregulated expression of TLR4 and COX-2 induced by LPS was obviously downregulated. Furthermore, the phosphorylation of NF-κB/p65 was significantly decreased in LPS-stimulated cells after supplementation with RTF. Our study suggests that RTF exerts a significant inhibitory effect on the LPS-induced enhancement of the malignant behaviors of HCC cells via inactivation of TLR4/NF-κB signaling. RTF may be a promising chemotherapeutic agent to limit HCC development and inflammation-mediated metastasis.

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TLR4 increases the stemness and is highly expressed in relapsed human hepatocellular carcinoma

Cited by 24 publications

References 41 publications

Pattern recognition receptors in health and diseases

Pattern recognition receptors in health and diseases

Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential

Total flavonoids of Radix Tetrastigma suppress inflammation-related hepatocellular carcinoma cell metastasis

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