Low Expression of Nuclear Toll‐like Receptor 4 in Laryngeal Papillomas Transforming into Squamous Cell Carcinoma

Ilmarinen, Taru; Hagström, Jaana; Haglund, Caj; Auvinen, Eeva; Leivo, Ilmo; Pitkäranta, Anne; Aaltonen, Leena-Maija

doi:10.1177/0194599814549730

Cited by 15 publications

(14 citation statements)

References 24 publications

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“…Human patient material and in vivo models in rodents have been studied for the involvement of TLR4 in tumor progression, although the focus of these projects was mainly on the involvement of the innate immune system [ 38 ]; [ 19 ]; [ 21 ]; [ 39 , 40 ]; [ 16 ]. Studies in TLR4-deficient mice revealed that TLR4 has a supportive role in the development of chemically induced skin cancer through immune response [ 21 ]; [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

TLR4 as a negative regulator of keratinocyte proliferation

et al. 2017

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TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.

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Section: Discussionmentioning

confidence: 99%

TLR4 as a negative regulator of keratinocyte proliferation

et al. 2017

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“…However, we think that translocation of these membrane-bound TLRs to nucleus is due to increased amount of these proteins and related signaling activity. Low nuclear expression of TLR4 has been previously linked to development of laryngeal squamous cell carcinoma [ 27 ]. However, this finding was not confirmed by other techniques.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptors 1, 2, 4 and 6 in esophageal epithelium, Barrett's esophagus, dysplasia and adenocarcinoma

et al. 2016

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BackgroundToll-like receptors (TLRs) recognize microbial and endogenous ligands and have already shown to play a role in esophageal cancer. In this study, we evaluated especially TLRs that sense bacterial cell wall components in Barrett's esophagus, dysplasia and esophageal adenocarcinoma.MethodsTLRs 1, 2, 4 and 6 were stained immunohistochemically and assessed in esophageal specimens from patients with esophageal dysplasia (n = 30) or adenocarcinoma (n = 99). Structures and lesions were evaluated including normal esophagus (n = 88), gastric (n = 67) or intestinal metaplasia (n = 51) without dysplasia, and low-grade (n = 42) or high-grade dysplasia (n = 37), and esophageal adenocarcinoma (n = 99).ResultsWe found TLR1, TLR2, TLR4 and TLR6 expression in all lesions. TLR expression increased in Barrett's mucosa and dysplasia. There was profound increase of TLR expression from gastric- to intestinal-type columnar epithelium. In cancers, high nuclear and cytoplasmic staining of TLR4 associated with metastatic disease and poor prognosis.ConclusionsTLR1, TLR2, TLR4 and TLR6 are upregulated during malignant changes of esophageal columnar epithelium. Increased TLR4 expression associates with advanced stage and poor prognosis in esophageal adenocarcinoma.

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“…GO functions and pathways including mitosis and cell cycle as well as Wnt, JAK/STAT and Toll-like receptor signaling pathways were markedly altered in HNSCC compared with normal controls. The mutation, abnormal expression and modification of these GOs and pathways have been frequently reported in HNSCC and other cancer types ( 34 – 38 ). In tumor cells, the normal energy metabolism of aerobic respiration is replaced by glycolysis, which is harnessed for accumulating intermediates of macromolecule biosynthesis, known as the 'Warburg effect' ( 39 – 41 ).…”

Section: Discussionmentioning

confidence: 99%

Expression profile analysis of head and neck squamous cell carcinomas using data from The Cancer Genome Atlas

Zhan

et al. 2016

Molecular Medicine Reports

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Head and neck squamous cell carcinoma (HNSCC) is the major histological type of head and neck cancer and no curative treatments are currently available. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) has produced large-scale sequencing data, which provide unprecedented opportunities to reveal molecular mechanisms of cancer. The present study analyzed the mRNA and micro (mi)RNA expression data of HNSCC and normal control tissues released by the TCGA database using a bioinformatics approach to explore underlying molecular mechanisms. The mRNA and miRNA expression data were downloaded from the TCGA database and differentially expressed genes (DEGs) and miRNAs (DEMs) between HNSCC and normal head and neck tissues were identified using TwoClassDif. Subsequently, the gene functions and pathways which are significantly altered in HNSCC were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Regulatory networks among DEGs and DEMs were then constructed, and transcription factors (TFs) potentially regulating the DEGs and DEMs were determined and a TF - miRNA - gene network was established. A total of 2,594 significant DEGs (1,087 upregulated and 1,507 downregulated), and 25 DEMs (8 upregulated and 17 downregulated) were identified in HNSCC compared with normal control samples. These DEGs were significantly enriched in GOs and KEGG pathways such as mitosis, cell cycle, Wnt, JAK/STAT and TLR signaling pathway. CPBP, NF-AT1 and miR-1 were situated in the central hub of the TF - miRNA - gene network, underlining their central roles in regulatory processes specific for HNSCC. The present study enhanced the current understanding of the molecular mechanisms underlying HNSCC and may offer novel strategies for its prevention, diagnosis and treatment.

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Low Expression of Nuclear Toll‐like Receptor 4 in Laryngeal Papillomas Transforming into Squamous Cell Carcinoma

Abstract: The expression of TLR4 may serve as a predictive marker of malignant transformation in LPs. High immunoexpression of cytoplasmic TLR4 in LSCC was associated with a more aggressive disease.

Cited by 15 publications

References 24 publications

TLR4 as a negative regulator of keratinocyte proliferation

TLR4 as a negative regulator of keratinocyte proliferation

Toll-like receptors 1, 2, 4 and 6 in esophageal epithelium, Barrett's esophagus, dysplasia and adenocarcinoma

Expression profile analysis of head and neck squamous cell carcinomas using data from The Cancer Genome Atlas

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