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Cellular and Molecular Biology

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

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.

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Fig. 1: Gene expression profiling of MFs in colonic mucosa: IL-6 gene network is altered in CAFs when compared to N-MFs.
Fig. 2: Colonic myofibroblasts (MFs) are the major expressers of ADH1B in normal mucosa and this expression is lost in CAFs.
Fig. 3: ADH1B substrate RO is unable to downregulate LPS-induced IL-6 expression in CAFs.

Data availability

Accession code for Bulk RNAseq data is https://doi.org/10.6084/m9.figshare.20685118.v2.

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Acknowledgements

The authors acknowledge the GI Tissue Bank at the University of Utah Gastroenterology Division in the Department of Internal Medicine. This manuscript is dedicated to the memory of Mala Sinha who passed away prematurely and unexpectedly before the manuscript could be submitted and played a critical role in the analysis of the presented data.

Funding

The authors acknowledge grant support from: NIDDK (1R01DK103150 and R56 DK55783-10A1), NCI (1R01CA127229-01A2 NCATS (KL2TR000072 and ILTR000072), NCATS (TR000071), NCI (3R01-CA97959), NCI R01CA207051.

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RV, MC and RCM: conceptualisation, data acquisition, analysis, manuscript preparation; NSM: data analysis; JT, MS, PJ, JIS, PAA: data acquisition and analysis, clinical material support; BAL: data analysis and manuscript revision for important intellectual content; EJB, DWP and IVP: study concept and design, data analysis, manuscript preparation and revision for important intellectual content, funding acquisition.

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Correspondence to Irina V. Pinchuk.

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Villéger, R., Chulkina, M., Mifflin, R.C. et al. Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02066-0

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