Prognostic role of TLR4 and TLR2 in hepatocellular carcinoma

Kairaluoma, Valtteri; Kemi, Niko; Huhta, Heikki; Pohjanen, Vesa-Matti; Helminen, Olli

doi:10.1080/0284186x.2021.1877346

Cited by 6 publications

(5 citation statements)

References 25 publications

(34 reference statements)

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“… 338 The expression of TLR2 in liver cancer tissues is significantly higher than that in normal liver tissues, and the expression of TLR2 protein is related to some mutant genes that lead to the occurrence of HCC, such as p53, PIK3CA, and β-catenin. 339 – 342 In addition, Chew et al revealed that the expression of TLR3 has independent effects on tumor parenchyma and infiltrating NK cells, and the expression of these two parts is related to inhibiting tumor cell proliferation, promoting tumor cell death, and prolonging the survival rate of patients. 343 This indicates that TLR3 may directly act on tumor parenchymal cells, promote the recruitment and activation of NK cells, and exert antitumor effects.…”

Section: Prr-related Diseasesmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

731

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

731

515

View full text Add to dashboard Cite

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“…Investigations of the role of TLRs have uncovered various regulatory mechanisms that contribute to the increased production of pro-inflammatory and oncogenic molecules like cytokines (e.g., NANOG, Caspase-1, Ephrin-A1, NO, and BCL6). Thus, dysregulation of TLR4 has been associated with invasiveness and metastatic potential, as well as poor prognosis for individuals with HCC (123)(124)(125). Recent research demonstrated that high expression of TLR4 was associated with microvascular invasion in HCC (126).…”

Section: Pancreatic and Hepatocellular Cancersmentioning

confidence: 99%

Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives

Mukherjee,

Patra,

Behzadi

et al. 2023

Front. Immunol.

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Toll-like receptors (TLRs) serve as the body’s first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

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“…Unlike the higher expression of TLR4 in hepatitis and cirrhosis, the expression of TLR4 in liver samples of patients with hepatocarcinoma does not change ( 56 ). However, the level of TLR4 is higher in liver samples from relapsed HCC patients, indicating that TLR4 expression is a potential prognostic biomarker in HCC therapy ( 67 , 68 ). On the contrary, TLR3 expression is associated with longer survival in HCC patients.…”

Section: Toll-like Receptors In Nafld and Hccmentioning

confidence: 99%

Pattern recognition receptors in the development of nonalcoholic fatty liver disease and progression to hepatocellular carcinoma: An emerging therapeutic strategy

et al. 2023

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Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and has become the leading chronic liver disease worldwide. NAFLD is viewed as the hepatic manifestation of metabolic syndrome, ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to advanced fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of NAFLD progression is still not clear. Pattern recognition receptor (PRR)-mediated innate immune responses play a critical role in the initiation of NAFLD and the progression of NAFLD-related HCC. Toll-like receptors (TLRs) and the cyclic GMP-AMP (cGAMP) synthase (cGAS) are the two major PRRs in hepatocytes and resident innate immune cells in the liver. Increasing evidence indicates that the overactivation of TLRs and the cGAS signaling pathways may contribute to the development of liver disorders, including NAFLD progression. However, induction of PRRs is critical for the release of type I interferons (IFN-I) and the maturation of dendritic cells (DCs), which prime systemic antitumor immunity in HCC therapy. In this review, we will summarize the emerging evidence regarding the molecular mechanisms of TLRs and cGAS in the development of NAFLD and HCC. The dysfunction of PRR-mediated innate immune response is a critical determinant of NAFLD pathology; targeting and selectively inhibiting TLRs and cGAS signaling provides therapeutic potential for treating NALF-associated diseases in humans.

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Prognostic role of TLR4 and TLR2 in hepatocellular carcinoma

Cited by 6 publications

References 25 publications

Pattern recognition receptors in health and diseases

Pattern recognition receptors in health and diseases

Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives

Pattern recognition receptors in the development of nonalcoholic fatty liver disease and progression to hepatocellular carcinoma: An emerging therapeutic strategy

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