Helicobacter pylori cytotoxin-associated gene A activates tumor necrosis factor-α and interleukin-6 in gastric epithelial cells through P300/CBP-associated factor-mediated nuclear factor-κB p65 acetylation

Lin, Qiong; Xu, Hui; Chen, Xintao; Tang, Guorong; Gu, Liqun; Wang, Yehong

doi:10.3892/mmr.2015.4143

Cited by 15 publications

(10 citation statements)

References 59 publications

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“…The expression of acetylated P65 in the nucleus of CAFs differentiated from MSCs induced by gastric cancer exosomes was gradually upregulated as the induction time progressed. P65 acetylation usually relies on histone acetyltransferase P300 [33][34][35] ; therefore, we detected the expression of P300 in the nucleus of CAFs and found that P300 expression was also upregulated.…”

Section: Discussionmentioning

confidence: 88%

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

Zhao

et al. 2021

Cell Death Dis

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Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies.

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Section: Discussionmentioning

confidence: 88%

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

Zhao

et al. 2021

Cell Death Dis

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“…Therefore, H. pylori infection may inhibit AHR and AHRR expression in the stomach, and the in vitro and in vivo results supported this speculation. H. pylori infection stimulated stomach cells to produce proinflammatory factors 32 , 33 , and these cytokines exerted provital roles in the pathogenesis of H. pylori infection-associated gastric diseases, including gastritis and gastric cancer 34 , 35 , 36 , 37 . The current study demonstrated that silencing of AHR or AHRR promoted TNF, IL-8 and IL-1β secretion in human stomach cells after coculture with H. pylori .…”

Section: Discussionmentioning

confidence: 99%

Involvement of Aryl Hydrocarbon Receptor and Aryl Hydrocarbon Receptor Repressor in Helicobacter Pylori-related Gastric Pathogenesis

et al. 2018

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Background: Persistent Helicobacter pylori (H. pylori) infection leads to various gastric diseases. Multiple studies have demonstrated that aryl hydrocarbon receptor (AHR) plays roles in the antibacterial response and aryl hydrocarbon receptor repressor (AHRR) is downregulated in stomach cancer. However, the role of AHR or AHRR in H. pylori-related gastric diseases remains unclear.Aims: To investigate whether AHR or AHRR is involved in H. pylori-related gastric diseases.Methods: Patients with gastritis or gastric adenocarcinoma were enrolled randomly, and gastric tissue specimens were diagnosed pathologically. AHR, AHRR, and H. pylori infection status in tissues were detected by immunohistochemistry. Human gastric cells were cocultured with H. pylori. siRNAs were used to silence AHR or AHRR, and a C57bl/6 mouse model colonized by H. pylori was established. Protein expression was determined by western blotting analysis, and TNF, IL-8 and IL-1β in cell supernatants were measured by ELISA.Results: AHR and AHRR were expressed in gastritis tissues and gastric cancer tissues without H. pylori infection, and principally located in the cytoplasm and nucleus. AHR expression was significantly correlated with AHRR expression in gastric tissues without H. pylori infection (P=0.008). However, their expressions were negatively correlated with H. pylori infection status. H. pylori coculture inhibited AHR and AHRR expression in stomach mucosa in vitro and in vivo. Gastric cells produced more TNF, IL-8 and IL-1β when AHR or AHRR was silenced.Conclusions: This preliminary study indicates that AHR and AHRR may be involved in H. pylori-related gastric pathogenesis, and helps toward understanding of inflammation-initiated carcinogenesis of gastric cancer.

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“…H. pylori- induced gastric diseases can be activated by inflammatory cytokines, such as IL-1, TNF-α, IL-6, and IL-8 [22,23]. TNF-α, IL-6, and IL-8 are the well-known inflammatory factors among the cytokines secreted by gastric epithelial cells, and they can be induced by H. pylori [24,25]. In addition, dysfunction of CRY1 and CRY2 accelerated the progression of arthritis by promoting the secretion of TNF-α [26].…”

Section: Introductionmentioning

confidence: 99%

H. pylori infection induced BMAL1 expression and rhythm disorder aggravate gastric inflammation

Shao

et al. 2019

EBioMedicine

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BackgroundRhythm abnormalities are crucial for diverse diseases. However, their role in disease progression induced by Helicobacter pylori (H. pylori) remains elusive.MethodsH. pylori infection was used in in vivo and in vitro experiments to examine its effect on rhythmic genes. The GEO database was used to screen H. pylori affecting rhythm genes, and the effect of rhythm genes on inflammatory factors. Chromatin immunoprecipitation and dual luciferase assays were used to further find out the regulation between molecules. Animal models were used to confirm the relationship between rhythm genes and H. pylori-induced inflammation.FindingsBMAL1 disorders aggravate inflammation induced by H. pylori. Specifically, H. pylori induce BMAL1 expression in vitro and in vivo through transcriptional activation of LIN28A, breaking the circadian rhythm. Mechanistically, LIN28A binds to the promoter region of BMAL1 and directly activates its transcription under H. pylori infection. BMAL1 in turn functions as a transcription factor and enhances the expression of proinflammatory cytokine TNF-α, thereby promoting inflammation. Of note, BMAL1 dysfunction in the rhythm disorder animal model aggravates inflammatory response induced by H. pylori infection in vivo.InterpretationThese findings in this study imply the pathogenic relationship between BMAL1 and H. pylori. BMAL1 may serve as a potential diagnostic marker and therapeutic target for the early diagnosis and treatment of diseases related to H. pylori infection.FundNational Natural Science Foundation of China.

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Helicobacter pylori cytotoxin-associated gene A activates tumor necrosis factor-α and interleukin-6 in gastric epithelial cells through P300/CBP-associated factor-mediated nuclear factor-κB p65 acetylation

Cited by 15 publications

References 59 publications

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

Involvement of Aryl Hydrocarbon Receptor and Aryl Hydrocarbon Receptor Repressor in Helicobacter Pylori-related Gastric Pathogenesis

H. pylori infection induced BMAL1 expression and rhythm disorder aggravate gastric inflammation

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