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OLFM4 promotes the progression of intestinal metaplasia through MYH9/GSK3β/β-catenin pathway

ABSTRACT: Intestinal metaplasia (IM), precancerous lesions of gastric carcinoma (PLGC) induced by factors like nitrite, Helicobacter pylori, or bile acid, carries a high risk of progressing to gastric cancer. IM is categorized into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients with IIM are at a higher risk of developing gastric cancer, emphasizing its importance for early screening. Besides the diagnostic challenges, the mechanisms underlying its progression remain a mystery. OLFM4, a gene associated with stemness characteristics, has been linked to promoting gastric and colorectal cancers. Our investigation used pathological sections from two clinical centers, biopsies of IM tissues, PLGC cell models, animal models, and organoids to explore OLFM4's role in IIM. OLFM4 expression was observed highly in IIM, with superior diagnostic accuracy of IIM compared to CDX2 and MUC2 for the first time. OLFM4, along with MYH9, was highly expressed in IM organoids and PLGC animal models. OLFM4, in combination with MYH9, accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, finally promoting the proliferation and invasion abilities of PLGC cells. In conclusion, OLFM4 serves as a novel biomarker for IIM and is utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. This study provides new insights into the mechanisms of progression and a new target of therapy in intestinal metaplasia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251765 | GEO | 2024/01/01

REPOSITORIES: GEO

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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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OLFM4 promotes the progression of intestinal metaplasia through MYH9/GSK3β/β-catenin pathway

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