Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation

Busada, Jonathan T.; Ramamoorthy, Sivapriya; Cain, Derek W.; Xu, Xiaojiang; Cook, Donald N.; Cidlowski, John A.

doi:10.1172/jci123233

Cited by 33 publications

(58 citation statements)

References 60 publications

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“…Glucocorticoids stimulate gastric acid secretion in dogs ( 81 ) and mice through serum- and glucocorticoid-inducible kinase (SGK 1 ), which stimulates K + channels, such as KCNQ1 ( 327 ). Adrenalectomy induces oxyntic atrophy and gastric inflammation through the spontaneous activation of CXCR2 + monocytes in mice, suggesting that glucocorticoids are essential for gastric homeostasis ( 56 ). In human studies, glucocorticoids induce hypergastrinemia ( 308 ), but do not affect acid secretion ( 164 ).…”

Section: Regulation Of Gastric Acid Secretionmentioning

confidence: 99%

“…In human studies, glucocorticoids induce hypergastrinemia ( 308 ), but do not affect acid secretion ( 164 ). Glucocorticoids bind ligand-dependent transcription factors, namely, mineralocorticoid (MR or NR3C2) and glucocorticoid (GR or NR3C1) receptors, that are broadly expressed in gastric cells, including parietal cells ( 56 , 278 ). The activity of glucocorticoids is regulated by the balance of two subtypes of hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2), which either catalyze production of active glucocorticoids or inactivate them, respectively ( 63 ).…”

Section: Regulation Of Gastric Acid Secretionmentioning

confidence: 99%

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The Physiology of the Gastric Parietal Cell

Engevik

Kaji

Goldenring

2020

Physiological Reviews

137

103

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Parietal cells are responsible for gastric acid secretion, which aids in the digestion of food, absorption of minerals, and control of harmful bacteria. However, a fine balance of activators and inhibitors of parietal cell-mediated acid secretion is required to ensure proper digestion of food, while preventing damage to the gastric and duodenal mucosa. As a result, parietal cell secretion is highly regulated through numerous mechanisms including the vagus nerve, gastrin, histamine, ghrelin, somatostatin, glucagon-like peptide 1, and other agonists and antagonists. The tight regulation of parietal cells ensures the proper secretion of HCl. The H+-K+-ATPase enzyme expressed in parietal cells regulates the exchange of cytoplasmic H+ for extracellular K+. The H+ secreted into the gastric lumen by the H+-K+-ATPase combines with luminal Cl− to form gastric acid, HCl. Inhibition of the H+-K+-ATPase is the most efficacious method of preventing harmful gastric acid secretion. Proton pump inhibitors and potassium competitive acid blockers are widely used therapeutically to inhibit acid secretion. Stimulated delivery of the H+-K+-ATPase to the parietal cell apical surface requires the fusion of intracellular tubulovesicles with the overlying secretory canaliculus, a process that represents the most prominent example of apical membrane recycling. In addition to their unique ability to secrete gastric acid, parietal cells also play an important role in gastric mucosal homeostasis through the secretion of multiple growth factor molecules. The gastric parietal cell therefore plays multiple roles in gastric secretion and protection as well as coordination of physiological repair.

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Section: Regulation Of Gastric Acid Secretionmentioning

confidence: 99%

Section: Regulation Of Gastric Acid Secretionmentioning

confidence: 99%

The Physiology of the Gastric Parietal Cell

Engevik

Kaji

Goldenring

2020

Physiological Reviews

137

103

View full text Add to dashboard Cite

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“…As previously reported in other tissues (20), we confirmed that germline deletion of the ARE region results in the accumulation of TTP mRNA in the mouse gastric fundus at 2 months of age ( Figure 1A). We previously showed that adrenalectomy (ADX) rapidly induces spontaneous gastric inflammation and SPEM (25). We utilized bilateral ADX to assess gastric inflammation and SPEM development in TTP∆ARE mice ( Figure 1B).…”

Section: Ttp Suppresses Adrenalectomy-induced Gastric Inflammation Gmentioning

confidence: 99%

“…Macrophages have previously been shown to be required to induce SPEM development (25,31). Therefore, we next analyzed the differentially expressed gene (DEG) lists using Ingenuity Pathway Analysis (IPA) to assess transcripts associated with macrophage activation.…”

Section: Ttp Suppresses Adrenalectomy-induced Gastric Inflammation Gmentioning

confidence: 99%

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Tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammation

Busada

Kadka

Peterson

et al. 2021

Preprint

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Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous pro-inflammatory and oncogenic mRNAs. Here, we utilized a TTP-overexpressing model, the TTPΔARE mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). We found that TTPΔARE mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing revealed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Finally, we show that protection from gastric inflammation was only partially due to suppression of Tnf, a well-known TTP target. Our results demonstrate that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of pro-neoplastic gastric inflammation.

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Identification of collagen subtypes of gastric cancer for distinguishing patient prognosis and therapeutic response

Wang,

Zhang,

Wang

et al. 2024

Cancer Innovation

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BackgroundGastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to collagen gene expression to indicate their prognosis and treatment response.MethodsWe collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA‐STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform‐independent collagen‐subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.ResultsWe identified two subtypes of gastric adenocarcinoma: a high‐expression collagen subtype (CS‐H) and a low‐expression collagen subtype (CS‐L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS‐L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3‐kinase (PI3K)/Akt pathways were transcriptionally active in the CS‐H subtype, while DNA repair activity was significantly greater in the CS‐L subtype. PIK3CA was frequently amplified in the CS‐H subtype, while PIK3C2A, PIK3C2G, and PIK3R1 were frequently deleted in the CS‐L subtype. CS‐H subtype tumors were more sensitive to fluorouracil, while CS‐L subtype tumors were more sensitive to immune checkpoint blockade. CS‐L subtype was predicted to be more sensitive to HER2‐targeted drugs, and CS‐H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway‐targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.ConclusionsWe classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transcriptome, and genetic alterations. The subtypes were closely related to patient responses to chemotherapy, immunotherapy, and targeted therapy.

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Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation

Cited by 33 publications

References 60 publications

The Physiology of the Gastric Parietal Cell

The Physiology of the Gastric Parietal Cell

Tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammation

Identification of collagen subtypes of gastric cancer for distinguishing patient prognosis and therapeutic response

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