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Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 1/2024

02-11-2023 | Colorectal Cancer | Original Article

Identification of Molecular Targets of Bile Acids Acting on Colorectal Cancer and Their Correlation with Immunity

Authors: Xi Yang, Ping Li, Jing Zhuang, Yinhang Wu, Zhanbo Qu, Wei Wu, Qichun Wei

Published in: Digestive Diseases and Sciences | Issue 1/2024

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Abstract

Background

Bile acids (BAs) are closely related to the occurrence and development of colorectal cancer (CRC), but the specific mechanism is still unclear.

Aims

To identify potential targets related to BAs in CRC and analyze the correlation with immunity.

Methods

The expression of BAs and CRC-related genes in TCGA was studied and screened using KEGG. GSE71187 was used for external validation of differentially expressed genes. Immunofluorescence, immunohistochemistry, and enzymatic cycling assays were used to detect the expression levels of the differentially expressed genes ki67 and BAs. Weighted gene coexpression network analysis (WGCNA) was used to identify genes associated with differential gene expression and immunity. The Cibersort algorithm was used to detect the infiltration of 22 kinds of immune cells in cancer tissues. The PPI network and ceRNA network were constructed to reveal the possible molecular mechanisms behind tumorigenesis.

Results

The BA-related gene UGT2A3 is positively correlated with good prognoses in CRC. The expression level of UGT2A3 was negatively related to the BA level and positively related to the Ki67 proliferation index. The expression level of UGT2A3 was higher in the moderately differentiation and advanced stage (stage IV) of CRC. In addition, the expression level of UGT2A3 is correlated with CD8+ T cells. A PPI network related to UGT2A3 and T-cell immune-related genes was constructed. A ceRNA network containing 32 miRNA‒mRNA and 40 miRNA‒lncRNA regulatory pairs was constructed.

Conclusion

UGT2A3 is a potential molecular target of bile acids in the regulation of CRC and is related to T-cell immunity.
Appendix
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Literature
1.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.PubMedCrossRef
2.
Imperiale TF, Ransohoff DF. Risk for colorectal cancer in persons with a family history of adenomatous polyps: a systematic review. Ann Intern Med. 2012;156:703–709.PubMedCrossRef
3.
Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–259.PubMedCrossRef
4.
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678–693.PubMedCrossRef
5.
6.
7.
Ochsenkühn T, Bayerdörffer E, Meining A et al. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer. 1999;85:1664–1669.PubMedCrossRef
8.
Reinehr R, Becker S, Eberle A, Grether-Beck S, Häussinger D. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem. 2005;280:27179–27194.PubMedCrossRef
9.
Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res. 2005;589:47–65.PubMedCrossRef
10.
Turner DJ, Alaish SM, Zou T, Rao JN, Wang JY, Strauch ED. Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression. Ann Surg. 2007;245:415–425.PubMedPubMedCentralCrossRef
11.
Campbell C, McKenney PT, Konstantinovsky D et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020;581:475–479.PubMedPubMedCentralCrossRef
12.
13.
Smyth GK. Limma: linear models for microarray data. In Bioinformatics and computational biology solutions using R and Bioconductor. Ed Gentlem R Carey V Dudoit Irizarry R Huber W.:420.
14.
Marisa L, de Reyniès A, Duval A et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453.PubMedPubMedCentralCrossRef
15.
16.
17.
18.
19.
The Gene Ontology Consortium. The gene ontology resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47:D330–D338.CrossRef
20.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS J Integr Biol. 2012;16:284–287.CrossRef
21.
Szklarczyk D, Gable AL, Lyon D et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–D613.PubMedCrossRef
22.
Breuer K, Foroushani AK, Laird MR et al. InnateDB: systems biology of innate immunity and beyond–recent updates and continuing curation. Nucleic Acids Res. 2013;41(Database issue):1228–1233.CrossRef
23.
Dweep H, Gretz N. miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat Methods. 2015;12:697.PubMedCrossRef
24.
Paraskevopoulou MD, Vlachos IS, Karagkouni D et al. DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts. Nucleic Acids Res. 2016;44:D231-238.PubMedCrossRef
25.
Tang Y, Li M, Wang J, Pan Y, Wu FX. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems. 2015;127:67–72.PubMedCrossRef
26.
Meech R, Hu DG, McKinnon RA et al. The UDP-glycosyltransferase (UGT) superfamily: new members, new functions, and novel paradigms. Physiol Rev. 2019;99:1153–1222.PubMedCrossRef
27.
Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581–616.PubMedCrossRef
28.
Hu DG, Marri S, Mackenzie PI, Hulin JA, McKinnon RA, Meech R. The expression profiles and deregulation of UDP-glycosyltransferase (UGT) genes in human cancers and their association with clinical outcomes. Cancers. 2021;13:4491.PubMedPubMedCentralCrossRef
29.
Wang S, Zhang C, Zhang Z et al. Transcriptome analysis in primary colorectal cancer tissues from patients with and without liver metastases using next-generation sequencing. Cancer Med. 2017;6:1976–1987.PubMedPubMedCentralCrossRef
30.
Court MH, Hazarika S, Krishnaswamy S, Finel M, Williams JA. Novel polymorphic human UDP-glucuronosyltransferase 2A3: cloning, functional characterization of enzyme variants, comparative tissue expression, and gene induction. Mol Pharmacol. 2008;74:744–754.PubMedCrossRef
31.
32.
Wang W, Zou W, Liu JR. Tumor-infiltrating T cells in epithelial ovarian cancer: predictors of prognosis and biological basis of immunotherapy. Gynecol Oncol. 2018;151:1–3.PubMedPubMedCentralCrossRef
33.
Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20:662–680.PubMedCrossRef
34.
Galon J, Costes A, Sanchez-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.PubMedCrossRef
35.
Tosolini M, Kirilovsky A, Mlecnik B et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–1271.PubMedCrossRef
36.
Srivastava S, Kern F, Sharma N et al. FABP1 and Hepar expression levels in Barrett’s esophagus and associated neoplasia in an Asian population. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2017;49:1104–1109.
37.
Liu S, Ni C, Li Y et al. The involvement of TRIB3 and FABP1 and their potential functions in the dynamic process of gastric cancer. Front Mol Biosci. 2021;8:790433.PubMedPubMedCentralCrossRef
38.
39.
Niccum DE, Billings JL, Dunitz JM, Khoruts A. Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2016;15:548–553.CrossRef
40.
Than BLN, Linnekamp JF, Starr TK et al. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene. 2017;36:3504.PubMedCrossRef
41.
Lu H, Cassis LA, Kooi CWV, Daugherty A. Structure and functions of angiotensinogen. Hypertens Res Off J Jpn Soc Hypertens. 2016;39:492–500.CrossRef
42.
Vincent F, Bonnin P, Clemessy M et al. Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. Cancer Res. 2009;69:2853–2860.PubMedCrossRef
43.
Sun S, Sun Y, Rong X, Bai L. High glucose promotes breast cancer proliferation and metastasis by impairing angiotensinogen expression. Biosci Rep. 2019;39:BSR20190436.PubMedPubMedCentralCrossRef
44.
Shimomoto T, Ohmori H, Luo Y et al. Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer. Clin Exp Metastasis. 2012;29:915–925.PubMedCrossRef
45.
Esmaeili M, Keshani M, Vakilian M et al. Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways. Gene. 2020;753:144796.PubMedCrossRef
46.
Qi X, Zhang DH, Wu N, Xiao JH, Wang X, Ma W. ceRNA in cancer: possible functions and clinical implications. J Med Genet. 2015;52:710–718.PubMedCrossRef
47.
Metadata
Title
Identification of Molecular Targets of Bile Acids Acting on Colorectal Cancer and Their Correlation with Immunity
Authors
Xi Yang
Ping Li
Jing Zhuang
Yinhang Wu
Zhanbo Qu
Wei Wu
Qichun Wei
Publication date
02-11-2023
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 1/2024
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-023-08032-x

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