Sox2 expression is maintained while gastric phenotype is completely lost in Cdx2-induced intestinal metaplastic mucosa☆

Mutoh, Hiroyuki; Sashikawa, Miho; Sugano, Kentaro

doi:10.1016/j.diff.2010.10.002

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…In transgenic mice SOX2 downregulation and CDX2 upregulation are overlapping processes, and SOX2 expression can still be observed in foci within IM where the gastric phenotype of the epithelium is lost 8. Accordingly, gene expression of SOX2 in our study is independent from the presence of IM.…”

Section: Discussionsupporting

confidence: 46%

Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa

et al. 2013

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The interplay between gastric and intestinal transcription factors has an important impact on gastric carcinogenesis. We compared the gene expression of CDX1, CDX2, SOX2 and related downstream genes in tumour and tumour surrounding gastric tissue of 48 gastric cancer patients with 30 healthy controls. There was no difference of gene expression of CDX1 and CDX2 between tumour or tumour-adjacent and tumour-distant mucosa, but both factors were significantly higher expressed in cancer patients compared with controls (p<0.01). SOX2 was downregulated in tumour tissue compared to controls, whereas tumour-adjacent and tumour-distant mucosa showed intermediate SOX2 expression. Laurén type and Helicobacter pylori infection had no significant impact on expression of the transcription factors. Expression of CDX1 and CDX2 was higher in the presence of intestinal metaplasia. The differential regulation of the gene expression of CDX1, CDX2 and SOX2 in patients with gastric cancer affects not only the tumour but also the non-neoplastic tumour-distant mucosa.

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Section: Discussionsupporting

confidence: 46%

Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa

et al. 2013

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“…Although several studies have investigated the relationship between SOX2 and CDX2, the mutual interaction of CDX2 and SOX2 in gastric IM progression is still unclear [16, 33, 34]. The above results indicated that SOX2 could significantly interfere with CDX2 transcriptional activity.…”

Section: Resultsmentioning

confidence: 99%

SOX2 interferes with the function of CDX2 in bile acid-induced gastric intestinal metaplasia

et al. 2019

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BackgroundIntestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer. Both animal and clinical studies have revealed that bile acid reflux and subsequent chronic inflammation are key causal factors of IM. Previous studies indicated that SOX2, the key transcription factor in gastric differentiation, was downregulated during IM development while CDX2, the pivotal intestine-specific transcription factor was upregulated significantly. However, it remains unclear whether the downregulation of SOX2 promotes gastric IM emergence or is merely a concomitant phenomenon. In addition, the underlying mechanisms of SOX2 downregulation during IM development are unclear.MethodsGastric cell lines were treated with deoxycholic acid (DCA) in a dose-dependent manner. The expression of CDX2 and miR-21 in gastric tissue microarray were detected by immunohistochemistry and in situ hybridization. Coimmunoprecipitation and immunofluorescence were performed to ascertain the interaction of SOX2 and CDX2. Luciferase reporter assays were used to detect the transcriptional activity of CDX2, and confirm miR-21 binding to SOX2 3′-UTR. The protein level of SOX2, CDX2 and downstream IM-specific genes were investigated using western blotting. mRNA level of miR-21, SOX2, CDX2 and downstream IM-specific genes were detected by qRT-PCR.ResultsBile acid treatment could suppress SOX2 expression and simultaneously induce expression of CDX2 in gastric cell lines. Furthermore, we demonstrated that SOX2 overexpression could significantly inhibit bile acid- and exogenous CDX2-induced IM-specific gene expression, including KLF4, cadherin 17 and HNF4α expression. In contrast, SOX2 knockdown had the opposite effect. A dual-luciferase reporter assay demonstrated that SOX2 overexpression could significantly suppress CDX2 transcriptional activity in HEK293T cells. CDX2 and SOX2 could form protein complexes in the nucleus. In addition, bile acid induced the expression of miR-21. The inhibition of SOX2 in bile acid-treated gastric cell lines was rescued by miR-21 knockdown.ConclusionsThese findings suggested that SOX2 can interfere with the transcriptional activity of CDX2 in bile acid-induced IM and that miR-21 might play a key role in this process, which shed new lights in the prevention of gastric cancer.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0739-8) contains supplementary material, which is available to authorized users.

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“…Ectopic activation of Sox2 in the hindgut suppresses the intestinal phenotype and induces features of the glandular stomach, but it does not repress Cdx2 itself [45]. Similarly, forced expression of Cdx2 in previously specified developing gastric epithelium is sufficient to induce intestinal metaplasia [46] but not down-regulation of Sox2 [47]. These findings that Sox2 and Cdx2 are not mutually repressive are interesting, given that they have dominant effects on gastric and intestinal differentiation.…”

Section: Specification Of Gastric Lineagementioning

confidence: 99%

Mechanisms of embryonic stomach development

McCracken

Wells

2017

Seminars in Cell & Developmental Biology

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The stomach is a digestive organ that has important roles in human physiology and pathophysiology. The developmental origin of the stomach is the embryonic foregut, which also gives rise a number of other structures. There are several signaling pathways and transcription factors that are known to regulate stomach development at different stages, including foregut patterning, stomach specification, and gastric regionalization. These developmental events have important implications in later homeostasis and disease in the adult stomach. Here we will review the literature that has shaped our current understanding of the molecular mechanisms that coordinate gastric organogenesis. Further we will discuss how developmental paradigms have guided recent efforts to differentiate stomach tissue from pluripotent stem cells.

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Sox2 expression is maintained while gastric phenotype is completely lost in Cdx2-induced intestinal metaplastic mucosa☆

Cited by 17 publications

References 29 publications

Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa

Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa

SOX2 interferes with the function of CDX2 in bile acid-induced gastric intestinal metaplasia

Mechanisms of embryonic stomach development

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