Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer
Menée à l'aide d'échantillons coliques (coliques normaux, polypes hyperplasiques, adénomes tubulaires, adénocarcinomes) et de (myo-)fibroblastes dérivés de tissus, cette étude met en évidence un mécanisme par lequel la perte de l'expression de l'alcool déshydrogénase 1B dans les fibroblastes associés au cancer favorise la progression tumorale en augmentant la production d'interleukine IL-6
Background : Increases in IL-6 by cancer-associated fibroblasts (CAFs) contribute to colon cancer progression, but the mechanisms involved in the increase of this tumor-promoting cytokine are unknown. The aim of this study was to identify novel targets involved in the dysregulation of IL-6 expression by CAFs in colon cancer. Methods : Colonic normal (N), hyperplastic, tubular adenoma, adenocarcinoma tissues, and tissue-derived myo-/fibroblasts (MFs) were used in these studies. Results : Transcriptomic analysis demonstrated a striking decrease in alcohol dehydrogenase 1B (ADH1B) expression, a gene potentially involved in IL-6 dysregulation in CAFs. ADH1B expression was downregulated in approximately 50% of studied tubular adenomas and all T1-4 colon tumors, but not in hyperplastic polyps. ADH1B metabolizes alcohols, including retinol (RO), and is involved in the generation of all-trans retinoic acid (atRA). LPS-induced IL-6 production was inhibited by either RO or its byproduct atRA in N-MFs, but only atRA was effective in CAFs. Silencing ADH1B in N-MFs significantly upregulated LPS-induced IL-6 similar to those observed in CAFs and lead to the loss of RO inhibitory effect on inducible IL-6 expression. Conclusion : Our data identify ADH1B as a novel potential mesenchymal tumor suppressor, which plays a critical role in ADH1B/retinoid-mediated regulation of tumor-promoting IL-6.