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

doi:10.1038/s41416-022-02066-0

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	537-548
Number of pages	12
Journal	British Journal of Cancer
Volume	128
Issue number	4
DOIs	https://doi.org/10.1038/s41416-022-02066-0
State	Published - Feb 16 2023

Bibliographical note

Funding Information:
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 Information:
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.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41416-022-02066-0

Cite this

Villéger, R., Chulkina, M., Mifflin, R. C., Markov, N. S., Trieu, J., Sinha, M., Johnson, P., Saada, J. I., Adegboyega, P. A., Luxon, B. A., Beswick, E. J., Powell, D. W., & Pinchuk, I. V. (2023). Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer. British Journal of Cancer, 128(4), 537-548. https://doi.org/10.1038/s41416-022-02066-0

@article{1010e0a285684c1b948b682403169cb2,

title = "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.",

author = "Romain Vill{\'e}ger and Marina Chulkina and Mifflin, {Randy C.} and Markov, {Nikolay S.} and Judy Trieu and Mala Sinha and Paul Johnson and Saada, {Jamal I.} and Adegboyega, {Patrick A.} and Luxon, {Bruce A.} and Beswick, {Ellen J.} and Powell, {Don W.} and Pinchuk, {Irina V.}",

note = "Funding Information: 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 Information: 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. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = feb,

day = "16",

doi = "10.1038/s41416-022-02066-0",

language = "English",

volume = "128",

pages = "537--548",

number = "4",

}

Villéger, R, Chulkina, M, Mifflin, RC, Markov, NS, Trieu, J, Sinha, M, Johnson, P, Saada, JI, Adegboyega, PA, Luxon, BA, Beswick, EJ, Powell, DW & Pinchuk, IV 2023, 'Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer', British Journal of Cancer, vol. 128, no. 4, pp. 537-548. https://doi.org/10.1038/s41416-022-02066-0

TY - JOUR

T1 - Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts

T2 - contribution to the increase of tumor-promoting IL-6 in colon cancer

AU - Villéger, Romain

AU - Chulkina, Marina

AU - Mifflin, Randy C.

AU - Markov, Nikolay S.

AU - Trieu, Judy

AU - Sinha, Mala

AU - Johnson, Paul

AU - Saada, Jamal I.

AU - Adegboyega, Patrick A.

AU - Luxon, Bruce A.

AU - Beswick, Ellen J.

AU - Powell, Don W.

AU - Pinchuk, Irina V.

N1 - Funding Information: 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 Information: 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. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/2/16

Y1 - 2023/2/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85143650547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85143650547&partnerID=8YFLogxK

U2 - 10.1038/s41416-022-02066-0

DO - 10.1038/s41416-022-02066-0

M3 - Article

C2 - 36482184

AN - SCOPUS:85143650547

VL - 128

SP - 537

EP - 548

IS - 4

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this