Conditional Deletion of IκB-Kinase-β Accelerates Helicobacter-Dependent Gastric Apoptosis, Proliferation, and Preneoplasia

Shibata, Wataru; Takaishi, Shigeo; Muthupalani, Sureshkumar; Pritchard, D. Mark; Whary, Mark T.; Rogers, Arlin B.; Fox, James G.; Betz, Kelly S.; Kaestner, Klaus H.; Karin, Michael; Wang, Yichen

doi:10.1053/j.gastro.2009.11.054

Cited by 65 publications

(46 citation statements)

References 41 publications

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“…Moreover, it has been demonstrated that the IKKbinduced NF-kB activation in myeloid cells is important for inflammatory responses and proliferation in the stomach after Helicobacter infection (38). Taken together, these results indicate that the TLR/MyD88/NF-kB signaling in BMDCs plays a key role in generating the inflammatory microenvironment in tumor tissues.…”

Section: Discussionsupporting

confidence: 59%

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: 59%

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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“…We found elevated apoptosis in infected Myd88 Ϫ/Ϫ mice in comparison to infected WT mice, suggesting involvement of MyD88 signaling in the regulation of apoptosis during infection with Helicobacter. Increased apoptosis in Myd88 Ϫ/Ϫ mice was followed by increased cell proliferation, which was similar to that reported in mice with a deletion in IKK␤ (23). The hyperproliferation we observed in Myd88 Ϫ/Ϫ mice was most likely in response to the high apoptotic rate in these mice, which is thought to be compensatory proliferation that is implicated in promoting carcinogenesis (30,31).…”

Section: Fig 4 Infection Of Myd88supporting

confidence: 72%

“…S2 in the supplemental material). Shibata et al (23) reported similar inflammation scores between WT mice and mice with a deletion in IKK␤, which is downstream of MyD88 signaling, in response to infection with H. felis. Together, these studies indicate that infiltration of immune cells into the mucosa and submucosa may not be the main factor responsible for the rapid development of premalignant and malignant lesions we observed in Myd88 Ϫ/Ϫ mice during infection.…”

Section: Myd88mentioning

confidence: 83%

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Deficiency of the Myeloid Differentiation Primary Response Molecule MyD88 Leads to an Early and Rapid Development of Helicobacter-Induced Gastric Malignancy

et al. 2014

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e Approximately 50% of the world's population is infected with Helicobacter pylori, leading to chronic inflammation, which increases the risk for gastric adenocarcinoma. MyD88 is a key adaptor molecule in inflammatory pathways involved in interleukin 1 (IL-1)/IL-18/Toll-like receptor signaling and has been shown to have divergent effects in carcinogenesis. The role of MyD88 in Helicobacter-induced gastric malignancy is unknown. Using a mouse model of Helicobacter-induced gastric cancer, we assessed the role of MyD88 in cancer development by evaluating gastric histopathology, apoptosis, proliferation, and cytokine expression. Infection of MyD88-deficient (Myd88 ؊/؊ ) mice with Helicobacter resulted in early and rapid advancement to gastric dysplasia as early as 25 weeks postinfection. The progression of Helicobacter-induced disease to precancerous and cancerous lesions in the absence of MyD88 signaling was accompanied by increased gastric epithelial apoptosis and proliferation. In addition, inflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), IL-6, and IL-1␤ were highly expressed in association with the development of gastric dysplasia. These data suggest that MyD88 signaling retards development and progression to cancer during Helicobacter infection. This is the first study to show evidence of MyD88 protection in an infection-driven inflammation-associated cancer model. Gastric cancer is the second most common cause of death from cancer worldwide, with 989,600 new cases each year (1). Helicobacter pylori is recognized as the major cause of gastric cancer (2, 3) and is classified as a group I carcinogen (2). The development of numerous human tumors is strongly linked to chronic inflammation, which is now recognized as a critical contributor to carcinogenesis (reviewed in references 4 and 5). While Helicobacter-induced chronic inflammation has also been linked to the development of gastric cancer, the mechanisms involved in this transition from inflammatory disease to gastric cancer remain unclear. Recently MyD88, which is a crucial mediator of inflammatory responses, has been the subject of vigorous investigation for its role in inflammation-associated cancers. MyD88 is a key adaptor molecule mediating signaling by most Toll-like receptors (TLRs) and that of proinflammatory cytokine interleukin 1 (IL-1) and IL-18 receptors (6, 7). Upon activation by their respective ligands, these receptors engage MyD88, resulting in downstream activation of nuclear factor B (NF-B), activator protein 1 (AP-1), and interferon regulatory factor 7 (IRF-7) signaling pathways (reviewed in reference 8), leading to stimulation of proinflammatory responses. Studies using inflammation-associated cancer models have reported opposing effects of MyD88 in carcinogenesis with protumor effects in liver (9), colorectal (10), and skin (11) cancers and antitumor effects in pancreatic (12) and colon (13) cancers. These contradictory findings highlight the complex role of MyD88 in carcinogenesis, which is ...

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“…Several reports suggested that inflammatory responses initiated by IL-1 play a pivotal role, and others showed that antiapoptotic pathways governed by IL-1 signaling were responsible for carcinogenic potential (51)(52)(53). Human single nucleotide polymorphism data also indicated the importance of IL-1␤ in the progression of gastric atrophy (5,54).…”

Section: Discussionmentioning

confidence: 96%

Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling

et al. 2016

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Histopathological changes of the gastric mucosa after Helicobacter pylori infection, such as atrophy, metaplasia, and dysplasia, are considered to be precursors of gastric cancer, yet the mechanisms of histological progression are unknown. The aim of this study was to analyze the histopathological features of the gastric mucosa in mice infected with H. pylori strain PMSS1 in relation to gastric stem cell marker expression. C57BL/6J mice infected with PMSS1 were examined for histopathological changes, levels of proinflammatory cytokines, and expression of stem cell markers. Histopathological gastritis scores, such as atrophy and metaplasia, and levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤), were increased after PMSS1 infection. Expression levels of the cell proliferation and stem cell markers CD44 and SOX9 were also significantly increased in PMSS1-infected mice. Importantly, almost all metaplastic cells induced by PMSS1 infection expressed SOX9. When IL-1 receptor (IL-1R) knockout mice were infected with PMSS1, metaplastic changes and expression levels of stem cell markers were significantly decreased compared with those in wild-type (WT) mice. In conclusion, H. pylori infection induced the expression of cytokines and stem cell markers and histopathological metaplasia in the mouse gastric mucosa. SOX9 expression, in particular, was strongly associated with metaplastic changes, and these changes were dependent on IL-1 signaling. The results suggested the importance of SOX9 in gastric carcinogenesis. Helicobacter pylori, a microaerophilic, spiral-shaped, Gramnegative bacterium, was first isolated in 1983 by Warren and Marshall (1). H. pylori colonizes the human gastric epithelium, causing atrophic gastritis and potentially triggering histological progression to carcinoma (2-4). Epidemiological studies have shown that cag pathogenicity island (PAI)-positive H. pylori strains are more likely to cause atrophic gastritis and gastric cancer than are cag PAI-negative strains (5-7).The cag PAI, a cluster of ϳ30 genes encoding a type IV secretion system (T4SS), is a major virulence factor of H. pylori. Studies of host cell signaling by H. pylori strains with the cag PAI revealed that important intracellular signaling cascades, including nuclear factor B (NF-B) and mitogen-activated protein kinase (MAPK), were especially activated by these types of strains (8, 9). Consequent upregulation and secretion of interleukin-8 (IL-8) from epithelial cells recruit activated neutrophils and monocytes into the lamina propria, where they secrete proinflammatory cytokines such as IL-1␤ and tumor necrosis factor alpha (TNF-␣) (10, 11).In animal models of H. pylori infection, the SS1 strain, which contains cagA genes, has been widely employed (12). However, it was recently revealed that the SS1 strain had a nonfunctional cag PAI and did not induce IL-8 or translocate CagA (13). In contrast, it was reported previously that the original human isolates, designated pre-mouse SS1 (P...

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Conditional Deletion of IκB-Kinase-β Accelerates Helicobacter-Dependent Gastric Apoptosis, Proliferation, and Preneoplasia

Cited by 65 publications

References 41 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

Deficiency of the Myeloid Differentiation Primary Response Molecule MyD88 Leads to an Early and Rapid Development of Helicobacter-Induced Gastric Malignancy

Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling

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