Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis

Kennedy, Catherine L.; Najdovska, Meri; Tye, Hazel; McLeod, Louise; Yu, Liang; Jarnicki, Andrew G.; Bhathal, Prithi S.; Putoczki, Tracy L.; Ernst, Matthias; Jenkins, Brendan J.

doi:10.1038/onc.2013.205

Cited by 47 publications

(36 citation statements)

References 29 publications

(63 reference statements)

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“…6E). We previously showed that TLR2/MyD88 signaling in tumor cells promotes gastric tumorigenesis in gp130 F/F mice (19,28). Consistent with these findings, it has been shown that TLR2 signaling in cancer cells plays a tumor-promoting role through the enhancement of stemness (23,24).…”

Section: Discussionsupporting

confidence: 62%

“…F/F mice, in which hyperactivation of Stat3 promotes gastric tumorigenesis via the TLR2/MyD88 cascade (19,28,29). The expression levels of Tnf, Cd14, Casp1, Il1a, and Tlr2 were significantly increased in gp130 F/F tumors; however, this upregulation was not suppressed in the gp130 F/F Myd88 À/À mouse tumors, in which Myd88 was disrupted in both epithelial and stromal cells ( Supplementary Fig.…”

Section: The Suppression Of the Inflammatory Responses In Gan Myd88mentioning

confidence: 98%

“…Mouse genetics studies have indicated that signaling through myeloid differentiation factor 88 (MyD88), which is an effector molecule of the TLRs, is required for the development of sporadic intestinal tumors (14)(15)(16), colitis-associated colon cancer (17,18), gastric cancer (19), liver cancer (20), skin tumors, and sarcomas (21).…”

Section: Introductionmentioning

confidence: 99%

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Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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It has been established that COX-2 and downstream signaling by prostaglandin E 2 (PGE 2 ) play a key role in tumorigenesis through generation of inflammatory microenvironment. Tolllike receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE 2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE 2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE 2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE 2 pathway will be an effective preventive strategy for gastric cancer.Cancer Prev Res; 9(3); 253-63. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 62%

Section: The Suppression Of the Inflammatory Responses In Gan Myd88mentioning

confidence: 98%

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Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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“…For example, autosomal recessive deficiencies of IRAK1 and MYD88 impair Toll-like receptor (TLR) to recurrent life-threatening bacterial diseases [59]. TIRAP is dispensable in TLR2 signalling at high ligand concentrations in macrophages and dendritic cells, with MyD88 probably coupling to the TLR2 receptor complex at sufficient levels to allow activation but having an inhibitory role in the signalling of TLR3 to JNK [60,61]. Although these results need to be validated through experimental investigation, they represent a promising direction for future studies.…”

Section: Discussionmentioning

confidence: 99%

Exploration of immunogene in colon cancer recurrence

Sun¹,

Yao²,

Yuan³

et al. 2018

Oncotarget

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Colon adenocarcinoma is the third most common cancer with high risk of recurrence and deteriorative consequences. Given the importance of immune genes in tumor regulation and cancer immunotherapy, there is a need to comprehensively profile the immunoregulatory genes from multiple types of colon cancer patient genomic data for discovering important associations and potential therapeutic targets of colon cancer recurrence. We used publicly available colon tumor tissue genomic data from The Cancer Genome Atlas database and immune genes data from innateDB database in this study. We derived the immune genes profiles by exploring multiple genomic profiles (gene expression, clinical and somatic mutation) in colon cancer. Some of the synthetic lethal genes we identified, such as CASP14, MS4A6E, KIR2DL1, KIR3DL1, KIR2DL3, CCL1, IL36B, FOXO3, POU2F1, SMAD3, HOXA9, PACS1, PROM1, DIDO1, SRC, CBFA2T2, NCOA6, PGAM1 and PROC, have been suggested to be potential targets correlated with immune genes for colon cancer recurrence treatment. Moreover, TLR2 could be promisingly new early stage indicator for colon adenocarcinoma recurrence. This is a systematic study that combines three different types of genomic data to molecularly characterize colon cancer and aims to identify potential targets for colon adenocarcinoma therapy. Meanwhile, the integrative analysis of immune genes for colon cancer could assist in identifying potential new symbols for colon adenocarcinoma recurrence.

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“…The normal samples were classed as the controls and the normalized data were analyzed using a t-test (20,21) implemented in LIMMA package (22). The differential genes in the metastatic and non-metastatic OS samples were considered to be those with a P-value <0.05.…”

Section: Methodsmentioning

confidence: 99%

Regulatory network of differentially expressed genes in metastatic osteosarcoma

Peng

Wang

Ding

et al. 2014

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the possible molecular mechanisms underlying the pathogenesis of metastatic osteosarcoma (OS), by examining the microarray expression profiles of normal samples, and metastatic and non-metastatic OS samples. The GSE9508 gene expression profile was downloaded from the Gene Expression Omnibus database, which included 11 human metastatic OS samples, seven non-metastatic OS samples and five normal samples. Pretreatment of the data was performed using the BioConductor package in R language, and the differentially expressed genes (DEGs) were identified by a t-test. Furthermore, function and pathway enrichment analyses of the DEGs were conducted using a molecule annotation system. A differential co-expression network was also constructed, and the submodules were screened using MCODE in Cytoscape. A total of 965 genes were identified as DEGs in metastatic OS. The DEGs were shown to participate in the regulation of DNA-dependent transcription, the composition of the nucleus, cytoplasm and membrane, and protein and nucleotide binding. Furthermore, the screened DEGs were significantly associated with the ribosome, axon guidance and the cytokine-cytokine receptor interaction pathway. Certain hub genes were identified in the constructed differential co-expression network, including matrix metalloproteinase 1 (MMP1), smoothened (SMO), ewing sarcoma breakpoint region 1 (EWSR1) and fasciculation and elongation protein ζ-1 (FEZ1). Brain selective kinase 2 (BRSK2) and aldo-keto reductase family 1 member B10 (AKRIB10) were present in the screened submodules. The results of the present study suggest that genes, including MMP1, SMO, EWSR1, FEZ1, BRSK2 and AKRIB10, may be potential targets for the diagnosis and treatment of metastatic OS. IntroductionOsteosarcomas (OS) are among the most frequently occurring secondary malignancies in childhood cancer (1). OS most often originates in the metaphyses of long bones in adolescents and young adults (2). During the past 30 years, an optimal treatment strategy for OS has been developed, which consists of multi-agent chemotherapy and aggressive surgical resection of all sites of disease involvement (3). However, ~80% of patients with localized OS develop metastatic disease following surgical resection (4). Patients with primary metastatic OS are a heterogeneous group, and a five-year event-free survival rate of up to 75% is reported for patients presenting with unilateral lung metastases (5). Furthermore <20% of patients with high-grade osteosarcoma are clinically diagnosed with metastatic disease at the initial diagnosis, and long-term survival rates of patients with metastatic OS range between 10-40% (6,7). Therefore, due to the high rate of systemic spread, complete recovery following surgical treatment alone is rare (8).Recently, microarray analysis (9) has been widely used in screening for differentially expressed genes (DEGs), in order to identify potential genes that may be investigated for the treatment of various human diseases (10,11)...

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Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis

Cited by 47 publications

References 29 publications

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Exploration of immunogene in colon cancer recurrence

Regulatory network of differentially expressed genes in metastatic osteosarcoma

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