Gene Summary

Gene:TLR3; toll like receptor 3
Aliases: CD283, IIAE2
Summary:The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It may thus play a role in host defense against viruses. Use of alternative polyadenylation sites to generate different length transcripts has been noted for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:toll-like receptor 3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TLR3 (cancer-related)

Benonisson H, Sow HS, Breukel C, et al.
High FcγR Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy.
J Immunol. 2018; 201(12):3741-3749 [PubMed] Related Publications
Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8

Chen L, Feng Z, Yue H, et al.
Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA.
Nat Commun. 2018; 9(1):4585 [PubMed] Free Access to Full Article Related Publications
People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner.

Mosaad YM, Metwally SS, Farag RE, et al.
Association between Toll-Like Receptor 3 (TLR3) rs3775290, TLR7 rs179008, TLR9 rs352140 and Chronic HCV.
Immunol Invest. 2019; 48(3):321-332 [PubMed] Related Publications
BACKGROUND: Inconsistent results were reported on the association of TLRs polymorphisms with the risk of HCV infection and HCV-related diseases.
OBJECTIVE: to assess the relation between TLR3 rs3775290, TLR7 rs17900 and TLR9 rs352140 SNPs and chronic HCV in the Egyptian cohort and to study their relation to interferon response.
METHODS: TLR3 rs3775290, TLR7 rs179008 and TLR9 rs352140 gene polymorphisms were typed by RFLP for 100 patients with chronic HCV and 25 with HCC in addition to 100 healthy controls.
RESULTS: A significant higher frequency has been found for the CT genotype of TLR3 rs3775290 in chronic HCV infection (p < 0.001) and CC genotype and the combined genotype CC-AT-GA ♀ in controls (p < 0.001). Non-significant associations have been found for studied SNPs and HCC and response to interferon and also the viral load or the degree of fibrosis, however, the higher HCV viral load and the higher grade of fibrosis were associated with treatment failure (p < 0.001).
CONCLUSION: The heterozygous CT genotype of TLR3 rs3775290 may be a susceptibility risk factor for chronic HCV infection and the homozygous CC and the combined CC-AT-GA ♀ genotypes may be protective. The HCV viral load and the grades of liver fibrosis could be considered a risk factor for interferon treatment failure. It seems that the studied SNPs have no role in HCC development or failure of treatment. However, the small sample size is a limiting factor of the present study when interpreting the negative associations and that the current used cohort does not permit such conclusion.
ABBREVIATIONS: cHCV=chronic Hepatitis C virus, HCC=hepatocellular carcinoma, TLR=Toll like Receptor, RFLP=Restriction Fragment Length Polymorphism, SNP=Single Nucleotide Polymorphism, IFN-α= interferon alpha.

Mikulandra M, Kobescak A, Verillaud B, et al.
Radio-sensitization of head and neck cancer cells by a combination of poly(I:C) and cisplatin through downregulation of survivin and c-IAP2.
Cell Oncol (Dordr). 2019; 42(1):29-40 [PubMed] Related Publications
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers. Concurrent radio-chemotherapy is the standard of care for advanced tumors. However, there is a need for more efficient regimens with less side effects resulting from high doses. Therefore, we set out to explore the therapeutic potential of ternary combinations by bringing together irradiation, cis-platinum and a TLR3 agonist, poly(I:C), with the aim to reduce the dosage of each treatment. This approach is based on our previous work, which revealed a selective cytotoxic effect of TLR3 agonists against malignant cells when combined with other anti-neoplastic agents.
METHODS: We explored the survival of HNSCC-derived cells (Detroit 562, FaDu, SQ20B and Cal27) using MTT and caspase 3/7 activation assays. The radio-sensitization effects of poly(I:C) and cisplatin were assessed using Western blotting, cell cycle progression, ROS formation and qRT-PCR assays.
RESULTS: We found that the combination of poly(I:C) and cisplatin downregulated c-IAP2 and survivin expression, reduced cell survival, induced anti-apoptotic gene expression and apoptosis, increased ROS formation and induced G2/M cell cycle arrest in the HNSCC-derived cells tested.
CONCLUSIONS: Our results indicate that a combined poly(I:C) and cisplatin treatment reduces the survival and induces the radio-sensitivity of HNSCC-derived cells, thus providing a rationale for the development of novel strategies for the treatment of head and neck cancer.

Lin LL, Huang CC, Wu MT, et al.
Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.
Cancer Sci. 2018; 109(11):3494-3502 [PubMed] Free Access to Full Article Related Publications
The innate immune receptors, such as toll-like receptor 3 (TLR3), melanoma differentiation-associated 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), have been shown to be differentially expressed in neuroblastoma (NB) and promote dsRNA poly (I:C)-induced NB suppression in vitro and in vivo. However, the role of another important innate immune cytosolic sensor, laboratory of genetics and physiology 2 (LGP2), in the cancer behavior of NB remains unclear. Here, we demonstrated that the expression levels of LGP2 were either low or undetectable in all NB cell lines tested with or without MYCN amplification. LGP2 expression levels were significantly increased only in NB cells without MYCN amplification, including SK-N-AS and SK-N-FI after poly (I:C) treatment in vitro and in mouse xenograft models. Ectopic expression of LGP2 in NB cells significantly enhanced poly (I:C)-induced NB cell death associated with downregulation of MDA5, RIG-I, MAVS and Bcl-2, as well as upregulation of Noxa and tBid. By immunofluorescence analyses, LGP2 localized mainly in the cytoplasm of NB cells after poly (I:C) treatment. In human NB tissue samples, cytoplasmic LGP2 expression was positively correlated with histological differentiation and inversely correlated with MYCN amplification. Positive cytoplasmic LGP2 expression in tumor tissues could predict a favorable outcome in NB patients independent of other prognostic factors. In short, LGP2 was effective in promoting poly (I:C)-induced NB suppression and cytoplasmic LGP2 can serve as an independent favorable prognostic factor in NB patients.

Halec G, Scott ME, Farhat S, et al.
Toll-like receptors: Important immune checkpoints in the regression of cervical intra-epithelial neoplasia 2.
Int J Cancer. 2018; 143(11):2884-2891 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Toll-like receptors (TLRs) are innate immune defenders thought to be critical for the clearance of human papillomavirus (HPV) infections hence preventing the development of HPV-associated high-grade cervical intra-epithelial neoplasia (CIN2 or 3), a potential cervical cancer precursor. However, the role of TLRs in the regression of established cervical lesions, such as CIN2, is hindered by a lack of prospective design studies. Using SYBR green real-time PCR assays, we have examined the gene expression of TLR2, TLR3, TLR7, TLR8 and TLR9, in cytobrush collected endocervical cells of 63 women diagnosed with CIN2 at study entry (baseline) and followed over a 3-year period. Wilcoxon rank-sum test was used to examine the association between TLR expression levels, measured at baseline, and CIN2 outcome (regression vs. persistence/progression) over time. HPV genotyping was performed using Roche Linear Array Assay detecting 37 HPV types. Women with CIN2 regression showed significantly higher baseline levels of TLR2 (p = 0.006) and TLR7 (p = 0.007), as well as a non-significant trend for a higher TLR8 expression (p = 0.053) compared to women with CIN2 persistence/progression. Six women with CIN2 regression, who presented with an HR-HPV DNA-negative CIN2 lesion at study entry, had significantly higher baseline levels of TLR2 (p = 0.005), TLR7 (p = 0.013) and TLR8 (p = 0.012), compared to women with CIN2 persistence/progression, suggesting their role in clearance of HPV prior to clearance of the lesion. Our results confirm a key role of TLRs in regression of CIN2 and support the potential use of TLR-agonists for treatment of these lesions.

Diakowska D, Nienartowicz M, Grabowski K, et al.
Toll-like receptors TLR-2, TLR-4, TLR-7, and TLR-9 in tumor tissue and serum of the patients with esophageal squamous cell carcinoma and gastro-esophageal junction cancer.
Adv Clin Exp Med. 2019; 28(4):515-522 [PubMed] Related Publications
BACKGROUND: Stimulation of toll-like receptors (TLRs) has been linked to the development of esophageal and gastric cancers.
OBJECTIVES: The aim of the study was to evaluate the clinical significance of tissue expression and serum concentration of TLR-2, TLR-4, TLR-7 and TLR-9 in patients with esophageal squamous cell carcinoma and gastro-esophageal junction adenocarcinoma.
MATERIAL AND METHODS: The study group consisted of 97 individuals: 32 with esophageal squamous cell carcinoma, 27 with gastro-esophageal junction cancer, and 38 ageand gender-matched controls. The mRNA expression and protein concentration of TLRs in tissues and sera were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) tests.
RESULTS: In esophageal cancer patients, mRNA expressions of TLR-2, TLR-4 and TLR-7, and protein concentrations of all TLRs were significantly higher in tumor than in control tissue (p < 0.05). In esophageal cancer patients with lymph node metastasis, a tendency toward higher protein concentrations of tumor TLR-4 was observed. In gastro-esophageal junction adenocarcinoma subgroup, only the mRNA expression of TLR-7 and protein concentrations of TLR-4, TLR-7 and TLR-9 were significantly higher in tumors than in normal mucosa (p < 0.05). Protein concentration of TLR-9 was significantly higher in tumors of gastro-esophageal junction cancer with lymph node metastasis and depth of tumor invasion. Diagnostic potential of serum TLR-4 as a marker of gastro-esophageal junction cancer presence was reported.
CONCLUSIONS: We demonstrated differences in the expression patterns of TLRs between esophageal squamous cell carcinoma and adenocarcinoma of gastro-esophageal junction, and showed circulating TLR-4 to be a potential marker of gastro-esophageal junction cancer.

Ghosh R, Roy S, Franco S
PARP1 depletion induces RIG-I-dependent signaling in human cancer cells.
PLoS One. 2018; 13(3):e0194611 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
DNA Damage Response (DDR) and DNA repair pathways are emerging as potent, ubiquitous suppressors of innate immune signaling in human cells. Here, we show that human cells surviving depletion of the Single Strand Break (SSB) repair protein PARP1 undergo p21-dependent senescence or cell cycle checkpoint activation in the context of activation of innate immune signaling, or viral mimicry. Specifically, we observe induction of a large number of interferon-stimulated genes (ISGs) and multiple pattern recognition receptors (PRRs; including RIG-I, MDA-5, MAVS, TLR3 and STING) and increased nuclear IRF3 staining. Mechanistically, depletion of the double-stranded RNA (dsRNA) helicase RIG-I or its downstream effector MAVS specifically rescues ISG induction in PARP1-depleted cells, suggesting that the RIG-I/MAVS pathway is required for sustained ISG expression in this context. Experiments with conditioned media or a neutralizing antibody to the α/β-IFN receptor revealed that persistent ISG expression additionally requires an autocrine/paracrine loop. Finally, loss of PARP1 and radiation-induced DNA damage strongly synergize in the induction of p21 and ISGs. Overall, these findings increase our understanding of how PARP1 may suppress deleterious phenotypes associated to aging, inflammation and cancer in humans.

Sato Y, Motoyama S, Wakita A, et al.
TLR3 expression status predicts prognosis in patients with advanced thoracic esophageal squamous cell carcinoma after esophagectomy.
Am J Surg. 2018; 216(2):319-325 [PubMed] Related Publications
BACKGROUND: The relationship between Toll-like receptors (TLRs) and esophageal squamous cell carcinoma (ESCC) is not completely understood.
METHODS: RT-qPCR was used to evaluate the mRNA expression of TLR1-10 in 13 ESCC lines. We then used ESCC tissue microarray (TMA) to confirm expression of TLR3 protein in patients with ESCC.
RESULTS: All ESCC lines showed 10-60 times higher TLR3 mRNA expression than PBLs. High expression of TLR3 correlated with favorable 5-year overall survival (OS) and disease specific survival (DSS) among patients with ESCC after esophagectomy (p < 0.01). Additionally, In the adjuvant chemotherapy group, TLR3 high patients had significantly better 5-year OS compared to TLR3 low patients (60.2%, 34.4%, respectively) but not in the surgery alone group.
CONCLUSION: High TLR3 expression is an independent prognostic factor and has the potential to serve as a clinically useful marker of the need for adjuvant chemotherapy after esophagectomy in patients with advanced thoracic ESCC.

Sun M, Geng D, Li S, et al.
LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells.
Biol Chem. 2018; 399(4):387-395 [PubMed] Related Publications
We investigated thoroughly the effect of lncRNA PART1 on prostate cancer cells proliferation and apoptosis, through regulating toll-like receptor (TLR) pathways. LncRNA PART1 expression was also examined by quantitative real-time polymerase chain reactions (qRT-PCR) in human tissues and the cells lines LNCaP and PC3. After transfection with si-PART1 or control constructs, the cell viability was measured by MTS and colony formation assays. In addition, the apoptosis rate of the prostate cancer cells was validated by TUNEL staining. Relationships between lncRNA PART1 expression and TLR pathway genes were demonstrated by qRT-PCR and Western blotting. High levels of lncRNA PART1 expression were correlated with advanced cancer stage and predication of poor survival. LncRNA PART1 levels was increased in PCa cells treated with 5α-dihydrotestosterone (DHT), confirming PART1 was directly induced by androgen. Moreover, down-regulation of lncRNA PART1 inhibited prostate cancer cell proliferation and accelerated cell apoptosis. In addition, lncRNA PART1 induced downstream genes expression in TLR pathways including TLR3, TNFSF10 and CXCL13 to further influence prostate cancer cells, indicating its carcinogenesis on prostate cancer. LncRNA PART1 promoted cell proliferation ability and apoptosis via the inhibition of TLR pathways in prostate cancer. LncRNA PART1 could hence be considered as a new target in the treatment of prostate cancer.

Chen Y, Zhao J, Li D, et al.
TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling.
Yonsei Med J. 2018; 59(1):43-50 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
PURPOSE: Tripartite-motif-containing protein 56 (TRIM56) has been found to exhibit a broad antiviral activity, depending upon E3 ligase activity. Here, we attempted to evaluate the function of TRIM56 in multiple myeloma (MM) and its underlying molecular basis.
MATERIALS AND METHODS: TRIM56 expression at the mRNA and protein level was measured by qRT PCR and western blot analysis. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry analysis was performed to investigate the effect of TRIM56 on MM cell proliferation and apoptosis. The concentrations of interferon (IFN)-β, interleukin (IL)-6, and tumor necrosis factor-α in MM cell culture supernatants were detected with respective commercial ELISA kits. Western blot was employed to determine the effect of TRIM56 on toll-like receptor 3 (TLR3)/toll-IL-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) signaling pathway.
RESULTS: TRIM56 expression was prominently decreased in MM cells. Poly (dA:dT)-induced TRIM56 overexpression in U266 cells suppressed proliferation, induced apoptosis, and enhanced inflammatory cytokine production, while TRIM56 knockdown improved growth, diminished apoptosis, and inhibited inflammatory cytokine secretion in RPMI8226 cells. Moreover, TRIM56 knockdown blocked TLR3 signaling pathway. Furthermore, poly (I:C), a TLR3 agonist, markedly abolished TRIM56 depletion-induced increase of proliferation, decrease of apoptosis, and reduction of inflammatory factor in MM cells.
CONCLUSION: TRIM56 may act as a tumor suppressor in MM through activation of TLR3/TRIF signaling pathway, contributing to a better understanding of the molecular mechanism of TRIM56 involvement in MM pathogenesis and providing a promising therapy strategy for patients with MM.

Bugge M, Bergstrom B, Eide OK, et al.
Surface Toll-like receptor 3 expression in metastatic intestinal epithelial cells induces inflammatory cytokine production and promotes invasiveness.
J Biol Chem. 2017; 292(37):15408-15425 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Toll-like receptors (TLRs) are innate immune receptors for sensing microbial molecules and damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (poly(I:C)) bind and activate TLR3. This stimulation leads to recruitment of the adaptor molecule TRIF (Toll/IL-1 resistance (TIR) domain-containing adapter-inducing interferon β) and activation of the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNβ production. Here we report that, unlike non-metastatic intestinal epithelial cells (IECs), metastatic IECs express TLR3 and that TLR3 promotes invasiveness of these cells. In response to poly(I:C) addition, the metastatic IECs also induced the chemokine CXCL10 in a TLR3-, TRIF-, and IRF3-dependent manner but failed to produce IFNβ. This was in contrast to healthy and non-metastatic IECs, which did not respond to poly(I:C) stimulation. Endolysosomal acidification and the endosomal transporter protein UNC93B1 was required for poly(I:C)-induced CXCL10 production. However, TLR3-induced CXCL10 was triggered by immobilized poly(I:C), was only modestly affected by inhibition of endocytosis, and could be blocked with an anti-TLR3 antibody, indicating that TLR3 can still signal from the cell surface of these cells. Furthermore, plasma membrane fractions from metastatic IECs contained both full-length and cleaved TLR3, demonstrating surface expression of both forms of TLR3. Our results imply that metastatic IECs express surface TLR3, allowing it to sense extracellular stimuli that trigger chemokine responses and promote invasiveness in these cells. We conclude that altered TLR3 expression and localization may have implications for cancer progression.

Doorduijn EM, Sluijter M, Salvatori DC, et al.
Cancer Immunol Res. 2017; 5(8):642-653 [PubMed] Related Publications
One of the next challenges in cancer immunotherapy is the resistance of tumors to T-cell-based treatments through loss of MHC class I. Here, we show that under these circumstances, the Toll-like receptor (TLR)-7/8 ligand imiquimod, but not the TLR3 ligand poly I:C or TLR9 ligand CpG, mediated an effective antitumor response. The rejection of these immune-escaped cancers was mediated by NK cells and CD4

Li J, Rao H, Jin C, Liu J
Involvement of the Toll-Like Receptor/Nitric Oxide Signaling Pathway in the Pathogenesis of Cervical Cancer Caused by High-Risk Human Papillomavirus Infection.
Biomed Res Int. 2017; 2017:7830262 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Human papillomavirus (HPV) can activate Toll-like receptor (TLR)/nitric oxide (NO) signaling pathways; however, whether the TLR/NO pathway is involved in cervical cancer caused by high-risk HPV (HR-HPV) remains unclear. In this study, 43 HR-HPV-positive patients with cervical cancer (CC group), 39 HR-HPV-positive patients with a healthy cervix (HR-HPV group), and 33 HR-HPV-negative controls were recruited. NO concentration in cervical canal and expression of inducible NO synthase (iNOS) in cervical tissues were detected. Expressions of key TLR/NO pathway genes (TLR3/4/7/8, NF-

Li H, Li Q, Guo T, et al.
LncRNA CRNDE triggers inflammation through the TLR3-NF-κB-Cytokine signaling pathway.
Tumour Biol. 2017; 39(6):1010428317703821 [PubMed] Related Publications
Colorectal neoplasia differentially expressed (CRNDE), an oncogene, is highly expressed in many tumor cells and affects cellular proliferation, migration, invasion, and apoptosis. Its function and mechanism of action is a research hotspot. In this study, microarray analysis was performed to discover the differentially expressed genes in CRNDE over-expression cells. RT² Profiler PCR Array was used to study the expression of genes related to the toll-like receptor (TLR) pathway. We found that over-expression of CRNDE in astrocytes increased the expression of key factors in the toll-like receptor signaling pathway, especially toll-like receptor-3-mediated MyD88-independent pathway. Furthermore, it up-regulated expression levels of downstream transcription factor such as nuclear factor kappa B and numerous cytokines. In contrast, CRNDE knockdown in glioma U87MG cell line showed an opposite trend in the expression of the above-mentioned genes. We speculated that CRNDE might trigger inflammation to regulate tumorigenesis and tumor development through the toll-like receptor pathway.

Lau WH, Zhu XG, Ho SWT, et al.
Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells.
Oncotarget. 2017; 8(20):32884-32904 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyI:C. We showed that polyI:C stimulated pro-inflammatory cytokines associated with survival and metastasis in a cell type-specific manner. While A549 and NCI-H292 released high levels of IL6, IL8 and GRO, the NCI-H358 cells endogenously secretes abundant levels of these cytokines, and was not further induced by polyI:C. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyI:C, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyI:C and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyI:C-mediated killing and suppression of oncogenicity and metastasis. While polyI:C stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyI:C-mediated suppression of survival and metastasis. Taken together, polyI:C alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyI:C and anti-IL6 enhanced polyI:C-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway.

Maitra R, Augustine T, Dayan Y, et al.
Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer.
Oncotarget. 2017; 8(21):35138-35153 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene (40-45% of all patients). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a double stranded (ds) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors. Toll Like Receptor (TLR) 3, a member of the toll like receptor family of the host innate immune system is the pattern recognition motif for dsRNA pathogens. Using TLR3 expressing commercial HEK-BlueTM-hTLR3 cells we confirm that TLR3 is the host pattern recognition motif responsible for the detection of reovirus. Further, our investigation with KRAS mutated HCT116 cell line showed that effective expression of host TLR3 dampens the infection potential of reovirus by mounting a robust innate immune response. Down regulation of TLR3 expression with siRNA improves the anticancer activity of reovirus. In vivo experiments using human CRC cells derived xenografts in athymic mice further demonstrate the beneficial effects of TLR3 knock down by improving tumor response rates to reovirus. Strategies to mitigate the TLR3 response pathway can be utilized as a tool towards improved reovirus efficacy to specifically target the dissemination of KRAS mutated CRC.

Bernardo AR, Cosgaya JM, Aranda A, Jiménez-Lara AM
Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.
Apoptosis. 2017; 22(7):920-932 [PubMed] Related Publications
Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

Ding L, Ren J, Zhang D, et al.
The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects.
Mol Cancer Ther. 2017; 16(6):1068-1079 [PubMed] Related Publications
The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (

Al-Anazi MR, Matou-Nasri S, Abdo AA, et al.
Association of Toll-Like Receptor 3 Single-Nucleotide Polymorphisms and Hepatitis C Virus Infection.
J Immunol Res. 2017; 2017:1590653 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Toll-like receptor 3 (TLR3) plays a key role in innate immunity by recognizing pathogenic, double-stranded RNAs. Thus, activation of TLR3 is a major factor in antiviral defense and tumor eradication. Although downregulation of

Shirai K, Shimada T, Yoshida H, et al.
Interferon (IFN)-induced protein 35 (IFI35) negatively regulates IFN-β-phosphorylated STAT1-RIG-I-CXCL10/CCL5 axis in U373MG astrocytoma cells treated with polyinosinic-polycytidylic acid.
Brain Res. 2017; 1658:60-67 [PubMed] Related Publications
Interferon (IFN)-stimulated genes (ISGs) exert multiple functions in immune system. IFN-induced protein 35 (IFI35) is a member of ISGs, and has been suggested to regulate innate immune reaction. However, the physiological functions and pathological roles of IFI35 in the central nervous system are not characterized well. In the present study, we found that the expression of IFI35 was induced by a Toll-like receptor 3 (TLR3) ligand polyinosinic-polycytidylic acid (poly IC) in U373MG human astrocytoma cells. Knockdown of IFI35 using RNA interference resulted in increased expression of IFN-β, phosphorylated STAT1 (P-STAT1), retinoic acid-inducible gene-I (RIG-I), CXCL10 and CCL5 induced by poly IC. Poly IC-induced expression of CXCL10 and CCL5 was decreased by knockdown of RIG-I. These results suggest that IFI35 may negatively regulate the TLR3-IFN-β-P-STAT1-RIG-I-CXCL10/CCL5 axis in U373MG cells, and IFI35 may play a role at least partially in the regulation of innate immune reactions in astrocytes.

Misawa A, Takayama KI, Fujimura T, et al.
Androgen-induced lncRNA POTEF-AS1 regulates apoptosis-related pathway to facilitate cell survival in prostate cancer cells.
Cancer Sci. 2017; 108(3):373-379 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Although long non-coding RNAs (lncRNAs) have been associated with a variety of cancers, the interplay between lncRNAs and androgen receptor signaling in prostate cancer is still unclear. We identified an androgen-dependent lncRNA, POTEF-AS1, whose expression was regulated by androgen receptor in two androgen-dependent cells by using directional RNA sequencing analysis. POTEF-AS1 promoted cell growth, repressed genes related to the Toll-like receptor signaling and apoptosis pathways, and inhibited apoptosis in docetaxel-treated LNCaP cells. These findings suggest that POTEF-AS1 would play a key role in the progression of prostate cancer by repressing Toll-like receptor signaling.

Chen D, Xie W, Lu Y, et al.
Gene polymorphisms of TLR2 and TLR3 in HBV clearance and HBV-related hepatocellular carcinoma in a Chinese male population.
Int J Biol Markers. 2017; 32(2):e195-e201 [PubMed] Related Publications
BACKGROUND: The Toll-like receptor plays an essential role in controlling immunity and inflammation. This study was to investigate the relationships of genetic variants in TLR2 and TLR3 with hepatitis B virus (HBV) natural clearance and HBV-related hepatocellular carcinoma (HCC) risk in a Chinese male population.
METHODS: We analyzed 5 polymorphisms of TLR2 (rs3804099 and rs3804100) and TLR3 (rs5743305, rs3775296 and rs3775291) in a population consisting of 686 participants with HBV natural clearance, 293 chronic HBV carriers and 395 HBV-positive HCC patients, using the improved multiplex ligase detection reaction method.
RESULTS: After adjustment for age and smoking and drinking status, no associations were observed either between the 5 single-nucleotide polymorphisms (SNPs) and the HBV natural clearance participants, or between the 5 SNPs and HCC patients. Whereas the stratified analysis showed that under the dominant models, nondrinkers with TLR2 rs3804100 and participants younger than 40 years old with TLR3 rs3775291 were significantly associated with HCC risk when compared with persistent HBV carriers (adjusted odd ratio [OR] = 0.49, 95% confidence interval [95% CI], 0.31-0.78, p = 0.003; and adjusted OR = 0.50, 95% CI, 0.29-0.86, p = 0.013, respectively). Furthermore, the TTTCT haplotype was found to promote the progress of HBV clearance and inhibit development of HBV-related HCC (OR = 0.77, 95% CI, 0.61-0.97, p = 0.029; and OR = 0.72, 95% CI, 0.55-0.94, p = 0.016, respectively). And the CCACC and CCTCT haplotypes were observed to decrease susceptibility to HCC (OR = 0.64, 95% CI, 0.40-1.00, p = 0.048; and OR = 0.43, 95% CI, 0.28-0.68, p<0.001, respectively).
CONCLUSIONS: This study revealed that TLR2 rs3804100 and TLR3 rs3775291 polymorphisms may be protective factors for HBV-related HCC.

Xia L, Liu Y, Fu Y, et al.
Integrated analysis reveals candidate mRNA and their potential roles in uterine leiomyomas.
J Obstet Gynaecol Res. 2017; 43(1):149-156 [PubMed] Related Publications
AIM: Uterine leiomyomas (UL) are the most common pelvic tumors, and the etiology and pathophysiology are not well understood. We aimed to elucidate the genes responsible for UL development.
METHODS: Integrated analyses of four datasets of mRNA profiling for UL were performed. Functional annotation of differentially expressed genes (DEG) was used to systematically characterize the global expression profiles. The UL-specific protein-protein interaction network was constructed.
RESULTS: Integrated analysis led to the discovery of 2167 DEG (1042 upregulated and 1125 downregulated). The aberrant expression of NAV2, KIF5C, DCX, CAPN6, COL4A2, ALDH1A1, and DPT may play important roles in UL tumorigenesis. In addition, the dysregulation of MEST, LGALS3, and TLR3 may be involved in the progression of UL by a common mechanism. Functional annotation showed that extracellular matrix receptor interaction may be more active and cause the extracellular matrix abnormally formed in UL. Moreover, focal adhesion and cell adhesion molecules may play roles in the development of UL. Furthermore, chemokine signaling pathway and cytokine-cytokine receptor interaction were most probably involved in the development of UL.
CONCLUSION: In conclusion, our study observed that a set of aberrantly expressed genes and the related biochemical pathways may lead to transformation of normal myometrium in pathological focuses.

Matijevic Glavan T, Cipak Gasparovic A, Vérillaud B, et al.
Toll-like receptor 3 stimulation triggers metabolic reprogramming in pharyngeal cancer cell line through Myc, MAPK, and HIF.
Mol Carcinog. 2017; 56(4):1214-1226 [PubMed] Related Publications
Toll-like receptor 3 (TLR3) has a dual role in cancer; its activation can trigger apoptosis as well as stimulate cancer cell survival, proliferation, and progression. We have shown here that TLR3 activation can induce metabolic reprogramming in a pharyngeal cancer cell line, leading to increased aerobic glycolysis, cell migration, elevated levels of reactive oxidative species (ROS), and decreased anti-oxidative response. Key proteins in these signaling pathways are heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), pyruvate kinase M2 (PKM2), and CD44 variants, which were over-expressed after TLR3 stimulation. TLR3 activation also induced upregulation of different genes involved in cancer progression (VEGF, MMP9, uPAR) and enzymes involved in glycolytic pathway. Most of the observed effects were Myc-dependent; however, some of them were also connected with MAPK and HIF signaling pathways. Since TLR3 agonists are being investigated as potential novel cancer therapy adjuvants and apoptosis inducers, alone or in combination with other therapeutic options, data presented here suggest extreme caution before their introduction into clinical practice. The fact that TLR3 ligands [poly(I:C) and poly(A:U)] can also aid cancer survival and progression, through induction of metabolic reprogramming, emphasizes the need to investigate this particular topic. Our data suggest that the combination of TLR3 ligands with Myc or MAPK inhibitors may be a way to neutralize their undesirable effects while enhancing their anti-tumor effect. © 2016 Wiley Periodicals, Inc.

Han S, Xu W, Wang Z, et al.
Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-κB pathways in the oral squamous cell carcinoma microenvironment.
Oncotarget. 2016; 7(25):37773-37789 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Hypoxia is a prominent feature of the microenvironment of solid tumors and may contribute to tumor progression through the oxygen-sensitive transcriptional regulator hypoxia-inducible factor-1 (HIF-1). Chronic inflammation is another typical feature. Inflammatory mediators, including Toll-like receptors (TLRs) and nuclear factor-κB (NF-κB), play an important role in cancer development. Recent studies have revealed extensive cross-talk between hypoxia and inflammation signaling, though the mechanisms remain unclear. Our results confirm that TLR3 and TLR4 are highly expressed in oral squamous cell carcinoma (OSCC). Activation of TLR3 and TLR4 stimulated the expression of HIF-1 through NF-κB. In addition, HIF-1 increased the expression of TLR3 and TLR4 through direct promoter binding. Thus, the TLR/NF-κB pathway forms a positive feedback loop with HIF-1. These results indicate a novel cross-talk between the TLR/NF-κB and HIF-1 signaling, which may contribute to OSCC initiation and progression. With the elucidation of this novel mechanism, it might serve as a basis for future microenvironment targeted cancer therapy.

Kataki K, Borthakur P, Kumari N, et al.
Association of mRNA expression of toll-like receptor 2 and 3 with hepatitis B viral load in chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
J Med Virol. 2017; 89(6):1008-1014 [PubMed] Related Publications
During Hepatitis B virus infection, the pathogen sensors Toll-like receptors (TLRs) play a role in innate immunity system. The study aimed to investigate mRNA expression levels of TLR2 and TLR3 in Hepatitis B virus (HBV) mediated chronic hepatitis B (CHB), cirrhosis (CIRR), and hepatocellular carcinoma (HCC), and to correlate viral load with severity of these diseases and expression of TLRs. A total of 180 HBV DNA positive samples were selected for the study. HVB-DNA was detected by multiplex PCR. Viral load estimation was done by using the Ampisure HBV Quantitative kit as per manufacture instructions. Expression levels of TLR2 and TLR3 were determined by real time PCR. The viral load was estimated to be 6.64log

Takeda Y, Azuma M, Matsumoto M, Seya T
Tumoricidal efficacy coincides with CD11c up-regulation in antigen-specific CD8(+) T cells during vaccine immunotherapy.
J Exp Clin Cancer Res. 2016; 35(1):143 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Dendritic cells (DCs) mount tumor-associated antigens (TAAs), and the double-stranded RNA adjuvant Poly(I:C) stimulates Toll-like receptor 3 (TLR3) signal in DC, which in turn induces type I interferon (IFN) and interleukin-12 (IL-12), then cross-primes cytotoxic T lymphocytes (CTLs). Proliferation of CTLs correlates with tumor regression. How these potent cells expand with high quality is crucial to the outcome of CTL therapy. However, good markers reflecting the efficacy of DC-target immunotherapy have not been addressed.
METHODS: Using an EG7 (ovalbumin, OVA-positive) tumor-implant mouse model, we examined what is a good marker for active CTL induction in treatment with Poly(I:C)/OVA.
RESULTS: Simultaneous administration of Poly(I:C) and antigen (Ag) OVA significantly increased a minor population of CD8(+) T cells, that express CD11c in lymphoid and tumor sites. The numbers of the CD11c(+) CD8(+) T cells correlated with those of induced Ag-specific CD8(+) T cells and tumor regression. The CD11c(+) CD8(+) T cell moiety was characterized by its high killing activity and IFN-γ-producing ability, which represent an active phenotype of the effector CTLs. Not only a TLR3-specific (TICAM-1-dependent) signal but also TLR2 (MyD88) signal in DC triggered the expansion of CD11c(+) CD8(+) T cells in tumor-bearing mice. Notably, human CD11c(+) CD8(+) T cells also proliferated in peripheral blood mononuclear cells (PBMC) stimulated with cytomegalovirus (CMV) Ag.
CONCLUSIONS: CD11c expression in CD8(+) T cells reflects anti-tumor CTL activity and would be a marker for immunotherapeutic efficacy in mouse models and probably cancer patients as well.

Agrawal U, Kumari N, Mishra AK, et al.
Immune signature of urothelial cancer associated with grade, recurrence, and invasion.
Urol Oncol. 2016; 34(9):418.e17-26 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) is one of most common genitourinary malignancy and the spectrum of disease ranges from in situ lesions to muscle-invasive cancers. The non-muscle-invasive lesions have tendency to recur or progress to muscle-invasive disease. The study of the immune profile may identify immune determinants associated with high-grade, recurrence, and invasion in patients with UC.
METHODS: Pathway-focused RT(2) profiler arrays were used to screen patients with UC for dysregulation of candidate genes of Th1-Th2-Th3 and NFκB pathways, which were then validated by real-time polymerase chain reaction on tumor samples and correlated with grade, recurrence, and invasion of tumors to identify their role in predicting behavior of the tumor. The cytokines found associated with recurrence were then validated in urine of patients with UC.
RESULTS: IFNγ, IL2, IL4, IL10, IL17, CCL7, CTLA4, and SPP1 of the cytokine pathway and TLR4, TLR3, RELA, NFκB1, and MYD88 of the NFκB pathway were found differentially expressed in patients with urothelial cancer by array and quantative real-time polymerase chain reaction. Among these, IL10 and SPP1 were found consistently up-regulated in high-grade, invasive, and recurrent cases and up-regulated IL10 and CTLA4 were found associated with a short recurrence-free survival time (P = 0.001 and P = 0.065). Urinary IL10 concentration was significantly higher in both patients with cancer and cystitis compared with healthy controls, but the difference in concentration between patients with cancer and cystitis patients was not statistically significant. However, urinary CTLA4 concentrations were found to be significantly higher in urothelial cancer patients compared with healthy controls and cystitis cases and found to be associated with poor recurrence-free survival.
CONCLUSION: The study indicates that high urinary CTLA4 concentration raises the index of suspicion of recurrence in a known case of urothelial cancer and may be used as a surveillance marker.

Wang G, Zhang M, Li Y, et al.
Studying the Effect of Downregulating Autophagy-Related Gene LC3 on TLR3 Apoptotic Pathway Mediated by dsRNA in Hepatocellular Carcinoma Cells.
Cancer Res Treat. 2017; 49(1):230-245 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
PURPOSE: The purpose of this study is to examine the role of the double-stranded RNA (dsRNA) activated Toll-interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) signal pathway in triggering apoptosis in hepatocellular carcinoma (HCC) cells.
MATERIALS AND METHODS: First, siRNA targeted autophagy-related gene LC3 (pU6H1-LC3 siRNA and siLC3) and a dsRNA used as a Toll-like receptor 3 (TLR3) ligand was constructed and synthesized, respectively. Then, a human HCC cell line was transfected with dsRNA, siLC3, and cotransfected with siLC3 and dsRNA (siLC3+dsRNA), respectively. Finally, quantification real-time polymerase chain reaction, western blotting, and immunofluorescence staining were used in the HCC line (SMMC7721), and MTT assay, flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, and transmission electron microscopy were used in an HCC xenograft model of nude mice. Human umbilical vein endothelial cell tube forming assay, color Doppler ultrasonographic flow image examination, and CD34-positive microvessel density were used
RESULTS: Compared with untreated cells, the protein and mRNA expression of TLR3 and TRIF was up-regulated, in order, siLC3+dsRNA, dsRNA, and siLC3. Expression of LC3 was obviously down-regulated and the autophagosomes were significantly decreased in siLC3+dsRNA and siLC3, whereas in dsRNA (p < 0.05). LC3 and TRIF colocation was observed in HepG2 cells. Decreased cell viability, increased apoptosis, decrease in xenograft tumor volume, and angiogenesis potential were also observed in order (p < 0.05).
CONCLUSION: Suppression of intracellular autophagy resulted in decreased degradation of TRIF protein, which can promote triggering of apoptosis by the TLR3-TRIF pathway. dsRNA and siLC3 could play anticancer roles in coordination.

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