Abstract 2179: Bile acids downregulate the squamous differentiation program of esophageal cells
Bibliographic record
Abstract
Abstract Background: The lumen of the normal esophagus is covered by a nonkeratinized, stratified squamous epithelium. However, in individuals with prolonged gastroesophageal reflux disease the squamous epithelium is gradually replaced by a more acid-resistant metaplastic columnar epithelium known as Barrett's Esophagus (BE). BE is the strongest known risk factor for development of esophageal adenocarcinoma. Understanding the molecular mechanisms underlying the formation of BE is fundamental to the development of new and effective prevention and treatment strategies for patients with BE. Methods: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile acids or acid exposure. Differentially expressed genes were classified into major biological functions based on analysis using pathway and interaction network software programs. Array data were verified by quantitative PCR and western blot both in-vitro and in human biopsies from esophageal normal squamous and columnar epithelia. Results: Bile acids modulated expression of 218 genes (153 up and 65 down) and acid 112 genes (31 up and 81 down). Interestingly, genes involved in squamous differentiation formed the largest functional group of differentially expressed genes and consisted of 40 genes downregulated by bile acids exposure. Bile acids decreased expression of key squamous differentiation genes such as KRT10, KRTDAP and GRHL1 which was confirmed at both the mRNA and protein level as was increased expression of CDX2, a transcription factor key to the intestinal epithelial phenotype. Bile acids induced expression changes were also seen in genes involved in the pathways of cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling and lipid metabolism. Expression of DSG1, a target gene of GRHL1, and DKK1, a Wnt inhibitor, were confirmed to be respectively downregulated and upregulated by bile acids. Further, expression data from human columnar epithelial biopsies revealed low or no expression of KRT10, KRTDAP, DSG1 and GRHL1 compared to squamous epithelia. Finally, network analysis suggested that bile acids exposure modulated the transcription activity of CREB and bile acids induced phosphorylation of CREB was confirmed experimentally. Conclusion: We report for the first time that bile acids inhibit the squamous differentiation program of esophageal cells while inducing columnar differentiation via CDX2 expression possibly via CREB and Wnt signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2179. doi:10.1158/1538-7445.AM2011-2179
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".