STAT3-Driven Upregulation of TLR2 Promotes Gastric Tumorigenesis Independent of Tumor Inflammation

Tye, Hazel; Kennedy, Catherine L.; Najdovska, Meri; McLeod, Louise; McCormack, William; Hughes, Norman R.; Dev, Anouk; Sievert, William; Ooi, Chia Huey; Ishikawa, Tomo-o; Oshima, Hiroko; Bhathal, Prithi S.; Parker, Andrew E.; Oshima, Masanobu; Tan, Patrick; Jenkins, Brendan J.

doi:10.1016/j.ccr.2012.08.010

Cited by 249 publications

(308 citation statements)

References 59 publications

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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: 63%

“…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: 81%

“…The induction of TLR2 and CD14 expression in tumor cells by activated macrophages Among the MyD88-dependent upregulated genes in Gan mouse tumors, we focused on TLR2 and its coreceptor CD14 because we had previously demonstrated that epithelial TLR2 expression is important for gastric tumorigenesis in gp130 F/F mice (28). We found that the expression levels TLR2 and CD14 were increased significantly in human gastric cancer and Gan mouse tumor tissues which were a mixture of epithelial and stromal cells (Supplementary Fig.…”

Section: The Suppression Of Gastric Tumorigenesis By Myd88 Disruptionmentioning

confidence: 96%

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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: 63%

Section: The Suppression Of the Inflammatory Responses In Gan Myd88mentioning

confidence: 81%

Section: The Suppression Of Gastric Tumorigenesis By Myd88 Disruptionmentioning

confidence: 96%

See 1 more Smart Citation

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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“…In addition, a number of pharmacological studies have demonstrated crocetin to have multiple activities, including anti-inflammatory (35,36) and anti-oxidant (37,38) effects. Therefore, it was hypothesized that the anti-oxidant and anti-inflammatory effects of crocetin may also be considered to be involved in several synergistic antitumor mechanisms (39,40). Further in vivo studies are required to investigate in greater detail the mechanisms and pharmacokinetics of crocetin and to provide an experimental basis for the clinical application of the drug.…”

Section: D a Bmentioning

confidence: 99%

Crocetin induces apoptosis of BGC-823 human gastric cancer cells

Wang

et al. 2013

Molecular Medicine Reports

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Abstract. Gastric cancer (GC) is one of the most common types of gastrointestinal tumors worldwide, and the side effects of chemotherapeutic drugs and the resistance to chemotherapy remain problematic in its clinical treatment. Therefore, safe and effective novel agents are urgently required. The purpose of the present study was to investigate the crocetin-sensitive treatment of GC and its possible mechanisms. BGC-823 human GC cells were treated with crocetin. The effects of crocetin on the viability of the cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst 33258 dyeing and Rh123 staining were used to detect cell apoptosis. The BGC-823 cells were subjected to western blotting analysis for detection of cytochrome c and cleaved caspase-3 protein expression. Crocetin inhibited the proliferation of the GC cell line in a dose-and time-dependent manner. Apoptotic BGC-823 cells induced by crocetin were stained by Hoechst 33258 and observed under a light microscope for cell membrane staining of dense nuclei, nuclear pyknosis, fragmentation, chromatin condensation and highlighted nuclear membrane staining. This revealed a decline in the mitochondrial membrane potential of the BGC-823 cells. Crocetin also induced caspase-3 activation and cytochrome c translocation into the cytosol from the mitochondria. The results of this study indicate that crocetin induces the apoptosis of BGC-823 cells, and may be used as an effective agent in the treatment of GC.

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“…10 Moreover, mutation in the IL-6 and IL-11 coreceptor, gp130, results in gastric tumor development through activation of Stat3. 11,12 On the other hand, the role of TNF-a in gastric tumorigenesis has not yet been investigated using a genetic mouse model.…”

Section: Introductionmentioning

confidence: 99%

TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells

et al. 2013

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Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-a) is a proinflammatory cytokine, and polymorphism in the TNF-a gene increases the risk of gastric cancer. We herein investigated the role of TNF-a in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-a (Tnf) or TNF-a receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf À / À Gan and Tnfrsf1a À / À Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf À / À Gan mice and Tnfrsf1a À / À Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf þ / þ or Tnfrsf1a þ / þ Gan mice. These results indicate that TNF-a signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-a expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-a-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-a/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-a/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

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STAT3-Driven Upregulation of TLR2 Promotes Gastric Tumorigenesis Independent of Tumor Inflammation

Cited by 249 publications

References 59 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

Crocetin induces apoptosis of BGC-823 human gastric cancer cells

TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells

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