Roles of Toll-Like Receptor 3 in Human Tumors

Zheng, Xin; Li, Song; Yang, Hui

doi:10.3389/fimmu.2021.667454

Cited by 22 publications

(15 citation statements)

References 112 publications

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“…PolyIC binds to and activates toll-like receptor 3 (TLR3), a pathogen-associated molecular pattern receptor located on the cell membrane and within endosomes. This generates a number of immune cell effects, such as an interferon response and innate immune cell activation, the latter effect responsible for the use of polyIC as a vaccine adjuvant [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Law

Masle-Farquhar

et al. 2022

Breast Cancer Res

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Background The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. Methods To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan–Meier survival analysis with immunohistochemistry and flow cytometry. Results Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present. Conclusions These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Law

Masle-Farquhar

et al. 2022

Breast Cancer Res

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“…However, TLR3 can also be activated in non-immune cells, such as fibroblasts and vascular endothelial cells ( Pirher et al, 2017 ). Interestingly, there is growing evidence that TLR3 is also generated in cancer cells, and the generation of TLR3 in cancer cells may exert an opposite effect in different cancer progression ( Zheng et al, 2021 ). Therefore, we investigated TLR3 expression in different cancers and its effect on cancer prognosis.…”

Section: Discussionmentioning

confidence: 99%

TLR3 serves as a novel diagnostic and prognostic biomarker and is closely correlated with immune microenvironment in three types of cancer

Zou

Guo

2022

Front. Genet.

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Background: Toll-like receptor 3 (TLR3) plays an important role in both innate and adaptive immunity, but the prognostic value of TLR3 in heterogeneous tumors and the correlations between TLR3 expression and immune infiltration of heterogeneous tumors remain unclear.Methods: We investigated the expression of TLR3 in a variety of tumors and focused on the diagnostic and prognostic values of TLR3 in kidney renal clear cell carcinoma (KIRC), pancreatic adenocarcinoma (PAAD) and brain lower grade glioma (LGG) by GEPIA, DriverDBv3, UALCAN, TIMER, LinkedOmics, STRING, GeneMANIA and FunRich, as well as the possible mechanisms of TLR3 affecting tumor prognosis were discussed. Additionally, real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to validate TLR3 expression in early KIRC. We also compared the expression of TLR3 in the plasma of early KIRC patients and normal controls by enzyme linked immunosorbent assay (ELISA).Results: TLR3 expression was significantly different in multiple tumors compared with paracancerous nontumor tissues. Elevated expression of TLR3 contributed to the prolonged survival outcome in KIRC patients. Suppressed expression of TLR3 contributed to the prolonged survival outcome in LGG and PAAD patients. Moreover, TLR3 was significantly elevated in stage1, grade1 and N0 of KIRC. The expression and function of TLR3 in KIRC, LGG and PAAD were closely related to tumor immune microenvironment. TRAF6 was a key gene in the interactions between TLR3 and its interacting genes. Finally, the results of RT-qPCR and ELISA indicated that TLR3 expression levels were significantly raised in renal tissue and plasma of early KIRC patients.Conclusion: TLR3 has the potential to be a diagnostic biomarker of KIRC, LGG and PAAD as well as a biomarker for evaluating the prognosis of KIRC, LGG and PAAD, particularly for the early diagnosis of KIRC. TLR3 affects tumors mainly by acting on the immune microenvironment of KIRC, LGG and PAAD. These findings could lead to new insights into the immunotherapeutic targets for KIRC, LGG, and PAAD.

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“…Toll-like receptor 3 (TLR3) is an important member of the TLR family and is involved in double-stranded RNA binding and activation of the NF-κB signaling pathway. It has been reported as an oncogene involved in the proliferation of tumor cells that are highly expressed in head and neck, prostate, and breast cancers, as well as in hepatocellular carcinoma and multiple myeloma [ 43 ]. Poly(A)-specific ribonuclease (PARN), which removes adenosine residues from the poly(A) tails after catalyzing mRNA deadenylation, was upregulated in gastric cancer, acute leukemia, and small cell lung carcinoma [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Wang

Kuang

Ding

et al. 2022

Cancers

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Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.

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Roles of Toll-Like Receptor 3 in Human Tumors

Cited by 22 publications

References 112 publications

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

TLR3 serves as a novel diagnostic and prognostic biomarker and is closely correlated with immune microenvironment in three types of cancer

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

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