A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism
Siyuan Niu
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorKe Shi
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorXinying Yue
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorMiaoxin Pan
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorLina Song
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorLinglong Gu
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorYuqian Tan
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorXiaoping Miao
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Jianbo Tian
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
Correspondence Jianbo Tian, Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
Email: [email protected]
Jiang Chang, Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jiang Chang
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence Jianbo Tian, Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
Email: [email protected]
Jiang Chang, Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Email: [email protected]
Search for more papers by this authorSiyuan Niu
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorKe Shi
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorXinying Yue
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorMiaoxin Pan
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorLina Song
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorLinglong Gu
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorYuqian Tan
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Search for more papers by this authorXiaoping Miao
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Jianbo Tian
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China
Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
Correspondence Jianbo Tian, Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
Email: [email protected]
Jiang Chang, Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jiang Chang
Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence Jianbo Tian, Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
Email: [email protected]
Jiang Chang, Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Email: [email protected]
Search for more papers by this authorAbstract
All-trans retinoic acid (ATRA) is the natural and synthetic analogue of vitamin A, playing an essential tumor suppressive role in multiple cancers including the esophageal squamous cell carcinoma (ESCC). Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) exerts a critical regulator of ATRA levels through specific inactivation of ATRA to hydroxylated forms. Our previous exome-wide analyses revealed a rare missense variant in CYP26B1 significantly associated with ESCC risk in the Chinese population. However, it is still unclear whether there are common variants in CYP26B1 affect the susceptibility of ESCC and the tumor promotion role of CYP26B1 in vivo. In this research, we conducted a two-stage case-control study comprised of 5057 ESCC cases and 5397 controls, followed by a series of biochemical experiments to explore the function of CYP26B1 and its common variants in the tumorigenesis of ESCC. Intriguingly, we identified a missense variant rs2241057[A>G] in the fourth exon of CYP26B1 significantly associated with the ESCC risk (combined odds ratio = 1.28; 95% confidence interval = 1.15–1.42; p = 2.96 × 10−6). Through further functional analysis, we demonstrated that ESCC cells with the overexpression of rs2241057[G] had a significant lower level of retinoic acid, compared with the overexpression of rs2241057[A] or the control vector. In addition, the CYP26B1 overexpression and knock-out ESCC cells affected cell proliferation rate both in vitro and in vivo. These results highlighted the carcinogenicity of CYP26B1 related to the ATRA metabolism in ESCC risk.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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| mc23540-sup-0001-Supplementary_Table1.docx23.6 KB | Supporting information. |
| mc23540-sup-0002-Supplementary_Table2.docx14.1 KB | Supporting information. |
| mc23540-sup-0003-Supplementary_Table3.docx14.5 KB | Supporting information. |
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REFERENCES
- 1Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-249.
- 2Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018; 154(2): 360-373.
- 3Zhang S, Sun K, Zheng R, Zeng H, He J. Cancer incidence and mortality in China, 2015. J Natl Cancer Center. 2020; 1(1): 2-11.
10.1016/j.jncc.2020.12.001 Google Scholar
- 4Abnet CC, Freedman ND, Hu N, et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet. 2010; 42(9): 764-767.
- 5Wang LD, Zhou FY, Li XM, et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1. Nat Genet. 2010; 42(9): 759-763.
- 6Wu C, Hu Z, He Z, et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet. 2011; 43(7): 679-684.
- 7Wu C, Kraft P, Zhai K, et al. Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat Genet. 2012; 44(10): 1090-1097.
- 8Wu C, Wang Z, Song X, et al. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat Genet. 2014; 46(9): 1001-1006.
- 9Ni X, Hu G, Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr. 2019; 59(suppl 1): S71-S80.
- 10Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001; 1(3): 181-193.
- 11Schenk T, Stengel S, Zelent A. Unlocking the potential of retinoic acid in anticancer therapy. Br J Cancer. 2014; 111(11): 2039-2045.
- 12Li N, Lu Y, Li D, et al. All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma. PLoS One. 2017; 12(4):e0174555.
- 13Ying M, Wang S, Sang Y, et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene. 2011; 30(31): 3454-3467.
- 14Yin W, Song Y, Liu Q, Wu Y, He R. Topical treatment of all-trans retinoic acid inhibits murine melanoma partly by promoting CD8(+) T-cell immunity. Immunology. 2017; 152(2): 287-297.
- 15Isoherranen N, Zhong G. Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases. Pharmacol Ther. 2019; 204:107400.
- 16Catharine Ross A, Zolfaghari R. Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr. 2011; 31: 65-87.
- 17Chang J, Zhong R, Tian J, et al. Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma. Nat Genet. 2018; 50(3): 338-343.
- 18Barizzone N, Cagliani R, Basagni C, et al. An investigation of the role of common and rare variants in a large Italian multiplex family of multiple sclerosis patients. Genes. 2021; 12(10): 1607.
- 19Gibson G. Rare and common variants: twenty arguments. Nat Rev Genet. 2012; 13(2): 135-145.
- 20Chang J, Tan W, Ling Z, et al. Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat Commun. 2017; 8:15290.
- 21Li J, Chen Z, Tian L, et al. LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma. Gut. 2014; 63(11): 1700-1710.
- 22Goldman MJ, Craft B, Hastie M, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020; 38(6): 675-678.
- 23Iqbal S, Ge F, Li F, et al. PROST: AlphaFold2-aware sequence-based predictor to estimate protein stability changes upon missense mutations. J Chem Inf Model. 2022; 62(17): 4270-4282.
- 24Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010; 11: 548.
- 25Li Z, Li S, Luo M, et al. dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications. Nucleic Acids Res. 2022; 50(D1): D471-D479.
- 26Yang Y, Peng X, Ying P, et al. AWESOME: a database of SNPs that affect protein post-translational modifications. Nucleic Acids Res. 2019; 47(D1): D874-D880.
- 27Krivospitskaya O, Elmabsout AA, Sundman E, et al. A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis. Mol Med. 2012; 18(1): 712-718.
- 28Takahashi N, Saito D, Hasegawa S, Yamasaki M, Imai M. Vitamin A in health care: suppression of growth and induction of differentiation in cancer cells by vitamin A and its derivatives and their mechanisms of action. Pharmacol Ther. 2022; 230:107942.
- 29Osanai M, Sawada N, Lee GH. Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1. Oncogene. 2010; 29(8): 1135-1144.
- 30Bhattacharya N, Yuan R, Prestwood TR, et al. Normalizing microbiota-induced retinoic acid deficiency stimulates protective CD8(+) T cell-mediated immunity in colorectal cancer. Immunity. 2016; 45(3): 641-655.
- 31Brown GT, Cash BG, Blihoghe D, Johansson P, Alnabulsi A, Murray GI. The expression and prognostic significance of retinoic acid metabolising enzymes in colorectal cancer. PLoS One. 2014; 9(3):e90776.
- 32Chen PH, Lee KW, Chen CH, et al. CYP26B1 is a novel candidate gene for betel quid-related oral squamous cell carcinoma. Oral Oncol. 2011; 47(7): 594-600.
