TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

Bianchi, Francesca; Alexiadis, Spyridon; Camisaschi, Chiara; Truini, Mauro; Centonze, Giovanni; Milione, Massimo; Balsari, Andrea; Tagliabue, Elda; Sfondrini, Lucia

doi:10.3390/ijms21041440

Cited by 48 publications

(36 citation statements)

References 35 publications

(51 reference statements)

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“…The abnormal expression of TLR3 has been reported on various of cancer tissues (10,11). TLR3 has also been recognized as a favorable prognosis biomarker of lung cancer by activating apoptosis or promoting autophagy (12,13). TLR3 agonist enhanced T cell infiltration in lung tissue, which is essential for tumor immunity within the tumor microenvironment (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Methylation Regulation of TLR3 on Immune Parameters in Lung Adenocarcinoma

Tian

et al. 2021

Front. Oncol.

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This study aims to analyze the methylation regulation of TLR3 in lung adenocarcinoma (LUAD) and to explore the association of TLR3 expression with immune microenvironment. TLR3 has a decreased expression in LUAD tissues and low expression of TLR3 is not only associated with poor prognosis in patients with LUAD, but also can be used as a diagnostic marker. Bisulfite sequencing PCR (BSP) results showed that the methylation level in the promoter of TLR3 was negatively correlated with the level of TLR3 mRNA in LUAD tissues. TIMER analysis showed that TLR3 was negatively correlated with the tumor purity of LUAD and positively with immune cell infiltration to some extent. ESTIMATE analysis also suggested that TLR3 expression and its methylation had significant correlation with immune score. The lower immune scores were associated with the late stage of LUAD and poor prognosis. The high expression of TLR3 might inhibit the development of LUAD by activating apoptosis pathway. The proteins interacted with TLR3 were mainly involved in the apoptosis pathway and positively correlated with the key genes (MYD88, Caspase 8, BIRC3, PIK3R1) in this pathway. Therefore, TLR3 as a key biomarker for prognosis and diagnosis in LUAD, might be considered as a potential epigenetic and immunotherapeutic target.

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Section: Introductionmentioning

confidence: 99%

Methylation Regulation of TLR3 on Immune Parameters in Lung Adenocarcinoma

Tian

et al. 2021

Front. Oncol.

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“…In addition, in vivo anti-tumor effects of TLR3 ligand, Poly(I:C) are possibly mainly due to an induction of cell death upon direct stimulation of TLR3 by TLR3 ligand, Poly(I:C) [24] and also the recruitment of tumor-specific CD8+ T lymphocytes [71]. TLR3 ligand, Poly(I:C) stimulation has been reported to induce cell death on itself or combination with sensitizers in several cancers, but lack of evidence in CCA [18][19][20][21][22][23][24][25][26][27][28][29][30][31][33][34][35][36]. Our results did demonstrate for the first time that Poly(I:C) itself did not induce CCA cell death but only in the presence of Smac mimetic, an IAP antagonist [72], the combination treatment significantly triggered apoptosis with high synergism.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, TLR3 ligands have been studied in clinical trials as adjuvants for cancer immunotherapy to enhance cancer vaccine efficacy [15][16][17]. In addition to orchestrating inflammatory and immune responses, triggering TLR3 signaling by TLR3 ligands has been reported to directly kill various cancer cells such as breast cancer [18,19], melanoma [20,21], renal cell carcinoma (RCC) [22], prostate cancer [23,24], nasopharyngeal carcinoma [25,26], multiple myeloma [27], head and neck squamous cell carcinoma (HNSCC) [28][29][30], hepatocellular carcinoma (HCC) [31], neuroblastoma [32], non-small cell lung cancer (NSCLC) [33][34][35], and mesothelioma [36]. TLR3 ligands-mediated cell death is involved the formation of a signaling complex composed of TRIF, RIPK1, Fasassociated protein with death domain (FADD) and caspase-8, the death signaling complex also called ripoptosome [34,37].…”

Section: Introductionmentioning

confidence: 99%

Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma

et al. 2020

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Background Toll-like receptor 3 (TLR3) ligand which activates TLR3 signaling induces both cancer cell death and activates anti-tumor immunity. However, TLR3 signaling can also harbor pro-tumorigenic consequences. Therefore, we examined the status of TLR3 in cholangiocarcinoma (CCA) cases to better understand TLR3 signaling and explore the potential therapeutic target in CCA. Methods The expression of TLR3 and receptor-interacting protein kinase 1 (RIPK1) in primary CCA tissues was assayed by Immunohistochemical staining and their associations with clinicopathological characteristics and survival data were evaluated. The effects of TLR3 ligand, Poly(I:C) and Smac mimetic, an IAP antagonist on CCA cell death and invasion were determined by cell death detection methods and Transwell invasion assay, respectively. Both genetic and pharmacological inhibition of RIPK1, RIPK3 and MLKL and inhibitors targeting NF-κB and MAPK signaling were used to investigate the underlying mechanisms. Results TLR3 was significantly higher expressed in tumor than adjacent normal tissues. We demonstrated in a panel of CCA cell lines that TLR3 was frequently expressed in CCA cell lines, but was not detected in a nontumor cholangiocyte. Subsequent in vitro study demonstrated that Poly(I:C) specifically induced CCA cell death, but only when cIAPs were removed by Smac mimetic. Cell death was also switched from apoptosis to necroptosis when caspases were inhibited in CCA cells-expressing RIPK3. In addition, RIPK1 was required for Poly(I:C) and Smac mimetic-induced apoptosis and necroptosis. Of particular interest, high TLR3 or low RIPK1 status in CCA patients was associated with more invasiveness. In vitro invasion demonstrated that Poly(I:C)-induced invasion through NF-κB and MAPK signaling. Furthermore, the loss of RIPK1 enhanced Poly(I:C)-induced invasion and ERK activation in vitro. Smac mimetic also reversed Poly(I:C)-induced invasion, partly mediated by RIPK1. Finally, a subgroup of patients with high TLR3 and high RIPK1 had a trend toward longer disease-free survival (p = 0.078, 28.0 months and 10.9 months). Conclusion RIPK1 plays a pivotal role in TLR3 ligand, Poly(I:C)-induced cell death when cIAPs activity was inhibited and loss of RIPK1 enhanced Poly(I:C)-induced invasion which was partially reversed by Smac mimetic. Our results suggested that TLR3 ligand in combination with Smac mimetic could provide therapeutic benefits to the patients with CCA. Graphical abstract

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“…The molecular mechanism is Toll-Like Receptor 3 (TLR3, Table 1 ) agonists, and it was found that the activation of TLR3 in vitro can induce apoptosis in lung cancer cell lines. In addition, some studies support the use of TLR3 agonists in patients with non-small cell lung cancer (NSCLC) to reactivate the local innate immune response ( Bianchi et al, 2020 ).…”

Section: Launched and Ongoing Drugsmentioning

confidence: 99%

Insight Into the Prospects for RNAi Therapy of Cancer

et al. 2021

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RNA interference (RNAi), also known as gene silencing, is a biological process that prevents gene expression in certain diseases such as cancer. It can be used to improve the accuracy, efficiency, and stability of treatments, particularly genetic therapies. However, challenges such as delivery of oligonucleotide drug to less accessible parts of the body and the high incidence of toxic side effects are encountered. It is therefore imperative to improve their delivery to target sites and reduce their harmful effects on noncancerous cells to harness their full potential. In this study, the role of RNAi in the treatment of COVID-19, the novel coronavirus disease plaguing many countries, has been discussed. This review aims to ascertain the mechanism and application of RNAi and explore the current challenges of RNAi therapy by identifying some of the cancer delivery systems and providing drug information for their improvement. It is worth mentioning that delivery systems such as lipid-based delivery systems and exosomes have revolutionized RNAi therapy by reducing their immunogenicity and improving their cellular affinity. A deeper understanding of the mechanism and challenges associated with RNAi in cancer therapy can provide new insights into RNAi drug development.

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TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

Cited by 48 publications

References 35 publications

Methylation Regulation of TLR3 on Immune Parameters in Lung Adenocarcinoma

Methylation Regulation of TLR3 on Immune Parameters in Lung Adenocarcinoma

Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma

Insight Into the Prospects for RNAi Therapy of Cancer

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