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Published on: September 15, 2023
Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes
T Tsukamoto1, T Mizoshita, M Mihara
1Division of Oncological Pathology, Aichi Cancer Centre Research Institute, Nagoya, Japan. ttsukamt@aichi-cc.jp
Aims:
Other than ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, the molecular mechanisms underlying gastric and intestinal phenotypes of human stomach adenocarcinomas have yet to be clarified in detail. We have reported that Sox2, an HMG-box gastric transcription factor, is expressed in normal gastric mucosa and down-regulated in intestinal metaplasia.
Methods And Results:
We analysed mRNA levels of Sox2 and other differentiation markers in 50 surgically resected stomach adenocarcinomas, immunohistochemically classified into gastric (G), gastric-and-intestinal (GI)-mixed, solely intestinal (I), and null (N) types. Sox2 was found to be transcribed in G and GI-mixed type adenocarcinomas in accordance with MUC5AC and MUC6 expression, while Cdx1 and Cdx2 were up-regulated in GI-mixed and I types along with the expression of MUC2 and villin. In the N type, both gastric and intestinal transcription factors were suppressed. Immunohistochemistry confirmed expression of Sox2 in MUC5AC+ lesions and Cdx2 localization together with MUC2. A stomach adenocarcinoma cell line, KATOIII, demonstrated both MUC5AC and Sox2, although MUC5AC mRNA was not detected in the Sox2+ AGS cell line.
Conclusions:
Sox2 may play an important role in maintaining a gastric phenotype in stomach cancers as well as in normal tissue, in cooperation with other cofactor(s).
Insights
Sox2 maintains gastric cell identity in stomach adenocarcinomas. This gastric transcription factor is down-regulated in intestinal types, suggesting its role in gastric cancer phenotype.
Area of Science:
- Gastroenterology
- Molecular Biology
- Cancer Research
Background:
- The molecular mechanisms of gastric and intestinal phenotypes in stomach adenocarcinomas are not fully understood.
- Sox2, a gastric transcription factor, is normally present in gastric mucosa but reduced in intestinal metaplasia.
Purpose of the Study:
- To investigate the role of Sox2 and intestinal transcription factors (Cdx1, Cdx2) in different subtypes of stomach adenocarcinomas.
- To clarify the molecular mechanisms underlying gastric and intestinal phenotypes in these cancers.
Main Methods:
- Analysis of mRNA levels of Sox2, Cdx1, Cdx2, and differentiation markers (MUC5AC, MUC6, MUC2, villin) in 50 stomach adenocarcinomas.
- Immunohistochemical classification of tumors into gastric, mixed gastric-intestinal, intestinal, and null types.
- Validation using stomach adenocarcinoma cell lines (KATOIII and AGS).
Main Results:
- Sox2 expression correlated with gastric markers (MUC5AC, MUC6) in gastric and mixed types.
- Cdx1 and Cdx2 were upregulated in mixed and intestinal types, correlating with intestinal markers (MUC2, villin).
- Both gastric and intestinal transcription factors were suppressed in the null type.
Conclusions:
- Sox2 appears crucial for maintaining the gastric phenotype in stomach adenocarcinomas, similar to its role in normal gastric tissue.
- Sox2 may function in conjunction with other cofactors to preserve gastric cell identity in cancer.
