Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours
| Autor: | David C. Metz, Ritu Pandey, Tobias Else, Yana Zavros, Bryson W. Katona, Juanita L. Merchant, Julie Starr, Karen Rico, Yuliang Chen, Suzann Duan, Jayati Chakrabarti |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
inflammatory mediators RC799-869 Proinflammatory cytokine Stroma Intestinal Neoplasms gastrin Humans Medicine organoids Neuroendocrine cell biology Tumor Necrosis Factor-alpha business.industry Gastroenterology Chromogranin A RNA expression Diseases of the digestive system. Gastroenterology TNFalpha Pancreatic Neoplasms Neuroendocrine Tumors medicine.anatomical_structure Gastrinoma immunohistochemistry STAT protein Cancer research biology.protein RNA Neuroendocrine Tumours Immunohistochemistry Calcium Tumor necrosis factor alpha Interleukin 17 business Genome-Wide Association Study |
| Zdroj: | BMJ Open Gastroenterology BMJ Open Gastroenterology, Vol 8, Iss 1 (2021) |
| ISSN: | 2054-4774 |
| Popis: | ObjectiveGastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups.AimTo identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumours.DesignWhole exome sequencing and RNA-sequencing were performed on surgically resected GEP-NETs (discovery cohort). RNA transcript profiles available in the Gene Expression Omnibus were analysed using R integrated software (validation cohort). Digital spatial profiling (DSP) was used to analyse paraffin-embedded GEP-NETs. Human duodenal organoids were treated with 5 or 10 ng/mL of tumor necrosis factor alpha (TNFα) prior to qPCR and western blot analysis of neuroendocrine cell specification genes.ResultsBoth the discovery and validation cohorts of small intestinal neuroendocrine tumours induced expression of mesenchymal and calcium signalling pathways coincident with a decrease in intestine-specific genes. In particular, calcium-related, smooth muscle and cytoskeletal genes increased in DGASTs, but did not correlate with MEN1 mutation status. Interleukin 17 (IL-17) and tumor necrosis factor alpha (TNFα) signalling pathways were elevated in the DGAST RNA-sequencing. However, DSP analysis confirmed a paucity of immune cells in DGASTs compared with the adjacent tumour-associated Brunner’s glands. Immunofluorescent analysis showed production of these proinflammatory cytokines and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) by the tumours and stroma. Human duodenal organoids treated with TNFα induced neuroendocrine tumour genes, SYP, CHGA and NKX6.3.ConclusionsStromal–epithelial interactions induce proinflammatory cytokines that promote Brunner’s gland reprogramming. |
| Databáze: | OpenAIRE |
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