Single Cell Integration Characterises Gastric Cell Metaplasia in Inflammatory Intestinal Diseases
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ABSTRACT:
PROVIDER: PRJEB75407 | ENA |
REPOSITORIES: ENA
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Project description:Background: Intestinal metaplasia (IM) is a gastric precancerous lesion that precedes the development of gastric cancer in up to 3.77 cases/1000 person-years. It consists in a trans-differentiation process of gastric to intestinal tissue. Two histological subtypes exist, complete (CIM) and incomplete (IIM), the latter having higher progression rates to gastric cancer . Our objective was to identify molecular processes responsible for the tumoral transition from intestinal metaplasia to GC and the initial steps of this lesion Methods: We used expression microarray to compare the transcriptome of intestinal metaplasia subtypes that progress to gastric cancer (IIM-GC and CIM-GC) after a follow-up period with respect to those that do not progress (IIM control and CIM control). Also, IM-NoGC (IM control, comprising both IIM and CIM Control) was compared with healthy gastric mucosa. Differentially expressed genes were obtained and functional analyses (GSEA and IPA softwares) were performed. Some deregulated genes were validated by qPCR. Results: Histological subtypes of intestinal metaplasia that progress or not to GC differ less among them than to healthy mucosa. Incomplete intestinal metaplasia has a higher number of over-expressed carcinogenic genes and molecular processes than the complete subtype. Most relevant molecular processes and genes in this group include antigenic processing, inflammation, activation of cell cycle and cell proliferation, oncogenes and tumor suppressors. When IM-NoGC is compared with healthy gastric mucosa new identified transcripts include TRIM, TMEM, homeobox, transporters and nucleolar RNAs SNORDs116. We confirm previously reported processes such us intestinal differentiation, metabolism of lipids and of xenobiotics and identify new ones such as non tumoral Warburg effect and melatonin degradation. Conclusions: Differentially expressed genes and molecular processes have been identified for the first time in intestinal metaplasia that progress to gastric cancer. New genes and molecular processes have also been identified in intestinal metaplasia in comparison with healthy gastric mucosa.
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Project description:Purpose: The goals of this study are to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). Methods: we utilized the TTP∆ARE mouse model to examine whether TTP overexpression can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). Results: We found that TTP∆ARE mice were completely protected from ADX-induce 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. Conclusions: 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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Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199170 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199171 | GEO