Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer

Romain Villéger, Marina Chulkina, Randy C. Mifflin, Nikolay S. Markov, Judy Trieu, Mala Sinha, Paul Johnson, Jamal I. Saada, Patrick A. Adegboyega, Bruce A. Luxon, Ellen J. Beswick, Don W. Powell, Irina V. Pinchuk

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)537-548
Number of pages12
JournalBritish Journal of Cancer
Volume128
Issue number4
DOIs
StatePublished - Feb 16 2023

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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