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CHAI Long Long, XIAO Ying Xuan, MENG Ling Han, WANG Huan, FENG Xian Hong, GU Xiu Li, LI Qi Chang, XIONG Qian Tao, CHEN Bi Feng. The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population[J]. Biomedical and Environmental Sciences, 2021, 34(7): 572-576. doi: 10.3967/bes2021.079
Citation: CHAI Long Long, XIAO Ying Xuan, MENG Ling Han, WANG Huan, FENG Xian Hong, GU Xiu Li, LI Qi Chang, XIONG Qian Tao, CHEN Bi Feng. The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population[J]. Biomedical and Environmental Sciences, 2021, 34(7): 572-576. doi: 10.3967/bes2021.079

The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population

doi: 10.3967/bes2021.079
Funds:  This work was supported by grants from the Natural Science Foundation of Hubei Province [2019CFB756] and the Fundamental Research Funds for the Central Universities [WUT: 2020IB029]
More Information
  • Author Bio:

    CHAI Long Long, male, born in 1994, MSc, majoring in tumor biology

    XIAO Ying Xuan, female, born in 2000, BS, majoring in biotechnology

  • Corresponding author: CHEN Bi Feng, E-mail: cbifeng@whut.edu.cn; XIONG Qian Tao, E-mail: shuying1114@163.com; LI Qi Chang, E-mail: qc.li@whut.edu.cn
  • &These authors contributed equally to this work.
  • Received Date: 2020-12-19
  • Accepted Date: 2021-02-26
  • &These authors contributed equally to this work.
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  • [1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin, 2018; 68, 394−424. doi:  10.3322/caac.21492
    [2] Zhang M, Tuo JY, Li GC, et al. Cancer incidence and mortality in Hubei cancer registries, 2013. Cancer Res Prev Treat, 2018; 45, 414−9. (In Chinese
    [3] Harrison C. Cancer: IL-22: linking inflammation and cancer. Nat Rev Drug Discov, 2013; 12, 504. doi:  10.1038/nrd4058
    [4] Wolk K, Witte E, Witte K, et al. Biology of interleukin-22. Semin Immunopathol, 2010; 32, 17−31. doi:  10.1007/s00281-009-0188-x
    [5] Wang JD, Li CD, Wan FT, et al. The rs1550117 A>G variant in DNMT3A gene promoter significantly increases non-small cell lung cancer susceptibility in a Han Chinese population. Oncotarget, 2017; 8, 23470−8. doi:  10.18632/oncotarget.15625
    [6] Jiang RQ, Tan ZM, Deng L, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology, 2011; 54, 900−9. doi:  10.1002/hep.24486
    [7] Zhang WC, Chen YY, Wei HM, et al. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res, 2008; 14, 6432−9. doi:  10.1158/1078-0432.CCR-07-4401
    [8] Liu T, Peng LS, Yu PW, et al. Increased circulating Th22 and Th17 cells are associated with tumor progression and patient survival in human gastric cancer. J Clin Immunol, 2012; 32, 1332−9. doi:  10.1007/s10875-012-9718-8
    [9] Welter JF, Gali H, Crish JF, et al. Regulation of human involucrin promoter activity by POU domain proteins. J Biol Chem, 1996; 271, 14727−33. doi:  10.1074/jbc.271.25.14727
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The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population

doi: 10.3967/bes2021.079
Funds:  This work was supported by grants from the Natural Science Foundation of Hubei Province [2019CFB756] and the Fundamental Research Funds for the Central Universities [WUT: 2020IB029]
&These authors contributed equally to this work.
CHAI Long Long, XIAO Ying Xuan, MENG Ling Han, WANG Huan, FENG Xian Hong, GU Xiu Li, LI Qi Chang, XIONG Qian Tao, CHEN Bi Feng. The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population[J]. Biomedical and Environmental Sciences, 2021, 34(7): 572-576. doi: 10.3967/bes2021.079
Citation: CHAI Long Long, XIAO Ying Xuan, MENG Ling Han, WANG Huan, FENG Xian Hong, GU Xiu Li, LI Qi Chang, XIONG Qian Tao, CHEN Bi Feng. The rs2227481 C>T Polymorphism in the IL22 Gene Promoter Significantly Reduces the Risk of Liver, Lung, and Gastric Cancer in a Han Chinese Population[J]. Biomedical and Environmental Sciences, 2021, 34(7): 572-576. doi: 10.3967/bes2021.079
  • Cancer is a serious threat to public health and the economy worldwide. Statistical data from the World Health Organization (WHO) in 2018 have demonstrated that lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by gastric cancer (5.7% and 8.2%), and liver cancer (4.7% and 8.2%)[1]. The situation is similar for these three types of cancer in the Hubei province of China[2]. Interleukin-22 (IL22), a member of the IL-10 family, is regarded as a link between inflammation and cancer. Recent studies have shown that IL22 acts as a tumor promoter and may promote carcinogenesis rather than function in antitumor immunity[3]. Interestingly, evidence of IL22 involvement in carcinogenesis manifests as dysregulation of IL22 expression in patients with many common cancers, including those of the stomach, liver, lung, stoma gut, and skin[4]. Therefore, it is hypothesized that individuals carrying certain genetic variants in the IL22 gene are vulnerable to the challenge of dysimmunity and are more susceptible to cancer. To test this hypothesis, we adopted a two-stage case-control approach to explore the potential contribution of IL22 gene promoter polymorphisms to cancer susceptibility in a Chinese Han population of Hubei province, and further elucidated the specific mechanism underlying the contribution of associated polymorphisms to cancer susceptibility.

    A total of 1,490 cancer patients (liver/lung/gastric cancer: 480/550/460) and 800 healthy controls were enrolled in this study. All cancer patients were confirmed histopathologically and recruited from Hubei Cancer Hospital and Wuhan Xinzhou District People’s Hospital. Normal controls were selected from cancer-free individuals who visited Wuhan Xinzhou District People’s Hospital for regular physical examinations. All participants were biologically unrelated Han Chinese living in the Hubei province of China, and signed informed consent was obtained from all participants. Ethics approval for this study was granted by the ethics committee of Wuhan University of Technology.

    To focus on single nucleotide polymorphisms (SNPs) in the IL22 gene promoter region, we first retrieved the SNP list within 2,000 bp upstream of the IL22 gene in the NCBI dbSNP website (https://www.ncbi.nlm.nih.gov/snp). The potentially functional SNPs were screened out from the list using SNPinfo software (https://snpinfo.niehs.nih.gov/). Then, the SNPs in the second step, which were further confirmed using Alibaba2 software (http://gene-regulation.com/pub/programs/alibaba2/index.html?), were selected for genotyping in our experimental cohort using Sanger sequencing (Supplementary Table S1, available in www.besjournal.com). The sequencing diagrams of the selected SNPs are shown in Supplementary Figure S1 (available in www.besjournal.com).

    No.SNP IDChromosomePositionAlleleRegionDistance to
    TSS (bp)
    Genotyping assay (Sanger sequencing)
    1rs22274871266933859C/Apromoter311Amplification primer:
    5’-AGATTCTGCTTGTGACGG-3’ (Forward)
    5’-ATAGTTGTTGTAGGATTATTTGG-3’ (Reverse)
    Sequencing primer: 5’-AGATTCTGCTTGTGACGG-3’
    2rs22274861266933971G/Apromoter423
    3rs22274851266933980A/Gpromoter432
    4rs22274841266934196G/Apromoter648
    5rs22274831266934443A/Tpromoter895Amplification primer:
    5’-GGCAACCACCATTCTACTCTT-3’ (Forward)
    5’-CACGGACTCACTTTCCTACCA-3’ (Reverse)
    Sequencing primer: 5’-TAAGTTTGTCAATACTAATGC-3’
    6rs22274821266934487T/Gpromoter939
    7rs22274811266934608C/Tpromoter1,060
    8rs22275111266934623C/Tpromoter1,075
    9rs22274791266934713C/Tpromoter1,165
    10rs22274781266934889A/Gpromoter1,341
    11rs22274741266935253T/Cpromoter1705Amplification primer:
    5’-TGTAACAGAACACCGAAAT-3’ (Forward)
    5’-TACCCAAAGGATACAACAT-3’ (Reverse)
    Sequencing primer: 5’-TACCCAAAGGATACAACAT-3’
    12rs22274731266935305C/Tpromoter1757
    13rs22274721266935400T/Cpromoter1852

    Table S1.  Detailed information of the IL22 gene polymorphisms included in the present study

    Figure S1.  The genotyping diagrams of IL22 gene polymorphisms. (A) rs2227485, (B) rs2227484, (C) rs2227483, (D) rs2227481, (E) rs2227511, (F) rs2227479, (G) rs2227478, (H) rs2227473, and (I) rs2227472.

    After identifying an association between the rs2227481 polymorphism and cancer risk, we performed a functional study to elucidate the molecular mechanisms underlying the contribution of rs2227481 to cancer susceptibility. A dual luciferase assay was conducted to test the effect of rs2227481 on IL22 transcriptional activity. Quantitative real-time RT-PCR was performed to examine the effects of the rs2227473 genotype on IL22 mRNA expression. Surface plasma resonance (SPR) analysis and chromatin immunoprecipitation (ChIP) assays were conducted to test the POU2F3 (Oct-11) binding capacity of the rs2227481 alleles. These assays have been described in our previous study[5], and the primers used are presented in Supplementary Table S2, available in www.besjournal.com.

    AssaysPrimer information
    Dual luciferase assaypGL3-C allele (reporter plasmid): IL22 gene promoter fragment was amplified with 5’-CTAGCTAGCCACGTTATTGCAAATG-3’ (forward) and 5’-CCCAAGCTTTTAGAGCCCGGAGGGT-3’ (reverse), then the PCR products were inserted into the NheI and HindIII restriction sites of the pGL3-basic vector.pGL3-T allele (reporter plasmid): Site-directed mutagenesis of pGL3-C allele (reporter plasmid)
    Quantitative real-time RT-PCRIL22 gene: 5’-TGACGACCAGAACATCCAGA-3’ (forward)
         5’-AATCGCCTTGATCTCTCCAC-3’ (reverse)
    GAPDH gene: 5’-TGCACCACCAACTGCTTAGC-3’ (forward)
          5’-GGCATGGACTGTGGTCATGAG-3’ (reverse).
    SPR (surface plasma resonance) analysisrs2227481 [C] probe: 5’-ACCTCTATATTCCTATATTCCCTTC-3’ (forward)
             5’-GAAGGGAATATAGGAATATAGAGGT-3’
    (reverse)rs2227481 [T] probe: 5’-ACCTCTATATTCTTATATTCCCTTC-3’ (forward)
                 5’-GAAGGGAATATAAGAATATAGAGGT-3’ (reverse)
    ChIP (chromatin immunoprecipitation) assayIdentification of IL22 gene fragment: 5’-TTTTTAAATAATTTGAAGGTA-3’ (forward)
                    5’-ATTTCCAAATAATCCTATAAC-3’ (reverse)

    Table S2.  Information of the primers used in the functional analysis of rs2227481

    All statistical analyses were performed using SPSS software (version 15.0; SPSS Inc., Chicago, IL). Differences in age, sex, smoking status, and alcohol status between cancer patients and normal controls were compared using a two-sided χ2 test. Other differences were evaluated using the Student’s t-test. Data are expressed as mean ± standard deviation (SD) from at least three independent experiments. The association between IL22 gene polymorphisms and cancer risk was estimated using logistic regression analysis. The level of significance was set at P < 0.05, and Bonferroni correction was applied for multiple comparisons (P < 0.008, 0.05/6).

    The characteristics of the participants are shown in Table 1. Regular smoking was defined as smoking at least one cigarette per day on average over one year or having quit smoking for less than one year. Regular drinking was defined as drinking at least 100 mL of alcohol per day on average over one year or having quit drinking for less than one year. The distributions of age, sex, smoking status, and drinking status were not significantly different between cancer patients and normal controls (P > 0.05). These results suggest that cancer patients and normal controls could be used for comparison for study purposes.

    GroupAge, n (%)Gender, n (%)Smoking status, n (%)Drinking status, n (%)P-value1
    ≤ 60 years> 60 yearsMaleFemaleEverNeverEverNever
    Liver cancer
    patients
    (n = 480)
    280 (58.3)200 (41.7)343 (71.5)137 (28.5)140 (29.2)340 (70.8)158 (32.9)322 (67.1)0.1540.5170.2370.217
    Lung cancer
    patients
    (n = 550)
    306 (55.6)244 (44.4)373 (67.9)177 (32.1)150 (27.3)400 (72.7)170 (31.0)380 (69.0)0.6150.4510.6390.613
    Gastric cancer
    patients
    (n = 460)
    252 (54.8)208 (45.2)323 (70.3)137 (29.7)132 (28.8)328 (71.2)148 (32.1)312 (67.9)0.8550.8620.3230.344
    Normal controls
    (n = 800)
    434 (54.3)366 (45.7)558 (69.7)242 (30.3)209 (26.1)591 (73.9)237 (29.6)563 (70.4)
      Note. 1Two-sided χ2 test for the distributions of age (1st column), gender (2nd column), smoking status (3rd column), and drinking status (4th column) between liver/lung/gastric cancer patients and normal controls.

    Table 1.  Characteristics of participants in the present study

    In stage I, the 13 selected IL-22 gene promoter polymorphisms were genotyped in 300 cancer patients and 150 normal controls. Of the 13 SNPs, rs2227487, rs2227486, rs2227482, and rs2227474 did not show polymorphism. Among the remaining nine SNPs, only rs2227481 was significantly associated with the risk of liver, lung, and gastric cancer (Table 2). Specifically, the T allele was associated with a decreased risk of liver, lung, and gastric cancer susceptibility at P-values of 0.007, 0.001, and 0.003, respectively, with OR (95% CI) of 0.55 (0.35–0.85), 0.46 (0.29–0.72), and 0.51 (0.33–0.80), respectively, and TT+CT genotypes were associated with a lower risk of lung cancer than the CC genotype (P = 0.003, OR = 0.44, 95% CI = 0.26–0.75). Since there was no significant association between the other eight SNPs (rs2227485, rs2227484, rs2227483, rs2227511, rs2227479, rs2227478, rs2227473, and rs2227472) and cancer risk, they were eliminated in the stage II study (Supplementary Table S3, available in www.besjournal.com).

    GroupsnAllele and genotype
    (frequency, %)
    Logistic regression analysis
    [P, OR (95% CI)]1
    TCTTCTCCT vs. CTT vs. CCTT vs. CTCT vs. CCTT+CT vs. CCTT vs. CT+CC
    Stage I
     Liver cancer10036
    (18.0)
    164
    (82.0)
    1
    (1.0)
    34
    (34.0)
    65
    (65.0)
    0.007, 0.55
    (0.35–0.85)
    0.027, 0.10
    (0.01–0.77)
    0.076, 0.15
    (0.02–1.22)
    0.103, 0.64
    (0.38–1.09)
    0.026, 0.55
    (0.33–0.93)
    0.040, 0.12
    (0.02–0.91)
     Lung cancer10031
    (15.5)
    169
    (84.5)
    1
    (1.0)
    29
    (29.0)
    70
    (70.0)
    0.001, 0.46
    (0.29–0.72)
    0.023, 0.09
    (0.01–0.71)
    0.105, 0.18
    (0.02–1.44)
    0.015, 0.51
    (0.29–0.88)
    0.003, 0.44
    (0.26–0.75)
    0.040, 0.12
    (0.02–0.91)
     Gastric cancer10034
    (17.0)
    166
    (83.0)
    1
    (1.0)
    32
    (32.0)
    67
    (67.0)
    0.003, 0.51
    (0.33–0.80)
    0.025, 0.10
    (0.01–0.75)
    0.086, 0.16
    (0.02–1.30)
    0.051, 0.59
    (0.34–1.00)
    0.011, 0.51
    (0.30–0.86)
    0.040, 0.12
    (0.02–0.91)
     Normal controls15086
    (28.7)
    214
    (71.3)
    12
    (8.0)
    62
    (41.3)
    76
    (50.7)
    Stage II
     Liver cancer380166
    (21.8)
    594
    (78.2)
    17
    (4.5)
    132
    (34.7)
    231
    (60.8)
    0.005, 0.74
    (0.60–0.92)
    0.029, 0.52
    (0.29–0.93)
    0.233, 0.70
    (0.39–1.26)
    0.037, 0.75
    (0.58–0.98)
    0.136, 1.20
    (0.95–1.52)
    0.066, 0.59
    (0.33–1.04)
     Lung cancer450200
    (22.2)
    700
    (77.8)
    18
    (4.0)
    164
    (36.4)
    268
    (59.6)
    0.006, 0.76
    (0.62–0.92)
    0.011, 0.48
    (0.27–0.84)
    0.077, 0.60
    (0.33–1.06)
    0.092, 0.81
    (0.63–1.04)
    0.023, 0.75
    (0.59–0.96)
    0.022, 0.52
    (0.30–0.91)
     Gastric cancer360155
    (21.5)
    565
    (78.5)
    18
    (5.0)
    119
    (33.1)
    223
    (61.9)
    0.004, 0.73
    (0.59–0.90)
    0.056, 0.58
    (0.33–1.01)
    0.503, 0.82
    (0.46–1.47)
    0.012, 0.70
    (0.53–0.92)
    0.004, 0.68
    (0.53–0.89)
    0.144, 0.66
    (0.38–1.15)
     Normal controls650356
    (27.4)
    944
    (72.6)
    48
    (7.4)
    260
    (40.0)
    342
    (52.6)
    Stage I+II (pooled data)
     Liver cancer480202
    (21.0)
    758
    (79.0)
    18
    (3.8)
    166
    (34.5)
    296
    (61.7)
    < 0.001, 0.70
    (0.58–0.84)
    0.002, 0.42
    (0.25–0.73)
    0.058, 0.58
    (0.33–1.02)
    0.009, 0.73
    (0.57–0.93)
    0.001, 0.68
    (0.54–0.86)
    0.008, 0.48
    (0.28–0.82)
     Lung cancer550231
    (21.0)
    869
    (79.0)
    19
    (3.5)
    193
    (35.0)
    338
    (61.5)
    < 0.001, 0.70
    (0.58–0.84)
    0.001, 0.39
    (0.23–0.67)
    0.022, 0.53
    (0.31–0.91)
    0.010, 0.74
    (0.59–0.93)
    0.001, 0.69
    (0.55–0.86)
    0.002, 0.44
    (0.26–0.75)
     Gastric cancer460189
    (20.5)
    731
    (79.5)
    19
    (4.1)
    151
    (32.8)
    290
    (63.1)
    < 0.001, 0.68
    (0.56–0.82)
    0.004, 0.46
    (0.27–0.78)
    0.163. 0.68
    (0.39–1.17)
    0.002, 0.68
    (0.53–0.86)
    0.000, 0.64
    (0.51–0.81)
    0.019, 0.53
    (0.31–0.90)
     Normal controls800442
    (27.6)
    1158
    (72.4)
    60
    (7.5)
    322
    (40.3)
    418
    (52.2)
      Note. 1The OR (95% CI) and the corresponding P-value were calculated using logistic regression analysis, and adjusted for age, gender, smoking, and drinking status.

    Table 2.  The association between IL22 gene rs2227481 polymorphism and risk of liver, lung, and gastric cancer

    GroupsnAllele and genotype (frequency, %)Logistic regression analysis [P, OR (95% CI)]1
    121112221 vs. 211 vs. 2211 vs. 1212 vs. 2211+12 vs. 2211 vs. 12+22
    rs2227485 A/G (1-A, 2-G)
     Liver cancer10094
    (47.0)
    106
    (53.0)
    22
    (22.0)
    50
    (50.0)
    28
    (28.0)
    0.422, 0.86
    (0.60–1.24)
    0.422, 0.74
    (0.36–1.53)
    0.817, 0.93
    (0.49–1.75)
    0.477, 0.80
    (0.44–1.48)
    0.406, 0.78
    (0.44–1.40)
    0.627, 0.86
    (0.47–1.57)
     Lung cancer100103
    (51.5)
    97
    (48.5)
    26
    (26.0)
    51
    (51.0)
    23
    (23.0)
    0.855, 1.03
    (0.72–1.48)
    0.857, 1.07
    (0.52–2.21)
    0.818, 1.08
    (0.58–1.99)
    0.988, 1.00
    (0.53–1.88)
    0.951, 1.02
    (0.56–1.86)
    0.812, 1.07
    (0.60–1.92)
     Gastric cancer10095
    (47.5)
    105
    (52.5)
    23
    (23.0)
    49
    (49.0)
    28
    (28.0)
    0.488, 0.88
    (0.62–1.26)
    0.492, 0.78
    (0.38–1.60)
    0.974, 0.99
    (0.53–1.86)
    0.439, 0.79
    (0.43–1.45)
    0.406, 0.78
    (0.44–1.40)
    0.762, 0.91
    (0.50–1.66)
     Normal150152
    (50.7)
    148
    (49.3)
    37
    (24.7)
    78
    (52.0)
    35
    (23.3)
    rs2227484 G/A (1-G, 2-A)
     Liver cancer100177
    (88.5)
    23
    (11.5)
    78
    (78.0)
    21
    (21.0)
    1
    (1.0)
    0.865, 1.05
    (0.60–1.83)
    0.810, 1.35
    (0.12–15.09)
    0.939, 1.03
    (0.55–1.91)
    0.829, 1.31
    (0.11–15.41)
    0.813, 1.34
    (0.12–14.95)
    0.901, 1.04
    (0.57–1.91)
     Lung cancer100180
    (90.0)
    20
    (10.0)
    81
    (81.0)
    18
    (18.0)
    1
    (1.0)
    0.488, 1.23
    (0.69–2.19)
    0.787, 1.40
    (0.13–15.66)
    0.510, 1.24
    (0.65–2.36)
    0.787, 1.40
    (0.13–15.66)
    0.813, 1.34
    (0.12–14.95)
    0.488, 1.25
    (0.67–2.34)
     Gastric cancer100179
    (89.5)
    21
    (10.5)
    80
    (80.0)
    19
    (19.0)
    1
    (1.0)
    0.605, 1.16
    (0.66–2.06)
    0.794, 1.38
    (0.12–15.47)
    0.644, 1.16
    (0.62–2.19)
    0.891, 1.19
    (0.10–13.99)
    0.813, 1.34
    (0.12–14.95)
    0.616, 1.17
    (0.63–2.18)
     Normal150264
    (88.0)
    36
    (12.0)
    116
    (77.3)
    32
    (21.4)
    2
    (1.3)
    rs2227483 A/T (1-A, 2-T)
     Liver cancer100109
    (54.5)
    91
    (45.5)
    30
    (30.0)
    49
    (49.0)
    21
    (21.0)
    0.634, 1.09
    (0.76–1.56)
    0.656, 1.18
    (0.57–2.43)
    0.587, 1.18
    (0.65–2.13)
    1.000, 1.00
    (0.52–1.92)
    0.851, 1.06
    (0.57–1.97)
    0.565, 1.18
    (0.67–2.06)
     Lung cancer100111
    (55.5)
    89
    (44.5)
    31
    (31.0)
    49
    (49.0)
    20
    (20.0)
    0.487, 1.14
    (0.79–1.63)
    0.507, 1.28
    (0.62–2.65)
    0.513, 1.22
    (0.68–2.20)
    0.885, 1.05
    (0.54–2.03)
    0.705, 1.13
    (0.61–2.11)
    0.457, 1.24
    (0.71–2.16)
     Gastric cancer100107
    (53.5)
    93
    (46.5)
    29
    (29.0)
    49
    (49.0)
    22
    (22.0)
    0.798, 1.05
    (0.73–1.50)
    0.820, 1.09
    (0.53–2.24)
    0.669, 1.14
    (0.63–2.07)
    0.888, 0.96
    (0.50–1.82)
    1.000, 1.00
    (0.54–1.84)
    0.686, 1.12
    (0.64–1.97)
     Normal150157
    (52.3)
    143
    (47.7)
    40
    (26.7)
    77
    (51.3)
    33
    (22.0)
    rs2227511 C/T (1-C, 2-T)
     Liver cancer100167
    (83.5)
    33
    (16.5)
    69
    (69.0)
    29
    (29.0)
    2
    (2.0)
    0.726, 0.92
    (0.56–1.49)
    0.671, 0.65
    (0.09–4.73)
    0.837, 0.94
    (0.54–1.65)
    0.719, 0.69
    (0.09–5.19)
    0.683, 0.66
    (0.09–4.78)
    0.778, 0.92
    (0.53–1.60)
     Lung cancer100168
    (84.0)
    32
    (16.0)
    70
    (70.0)
    28
    (28.0)
    2
    (2.0)
    0.841, 0.95
    (0.58–1.55)
    0.682, 0.66
    (0.09–4.80)
    0.974, 0.99
    (0.56–1.74)
    0.694, 0.67
    (0.09–5.01)
    0.683, 0.66
    (0.09–4.78)
    0.910, 0.97
    (0.56–1.69)
     Gastric cancer100170
    (85.0)
    30
    (15.0)
    71
    (71.0)
    28
    (28.0)
    1
    (1.0)
    0.919, 1.03
    (0.62–1.69)
    0.813, 1.34
    (0.12–15.05)
    0.987, 1.01
    (0.57–1.77)
    0.818, 1.33
    (0.12–15.41)
    0.813, 1.34
    (0.12–14.95)
    0.955, 1.02
    (0.58–1.77)
     Normal150254
    (84.7)
    46
    (15.3)
    106
    (70.7)
    42
    (28.0)
    2
    (1.3)
    rs2227479 C/T (1-C, 2-T)
     Liver cancer100182
    (91.0)
    18
    (9.0)
    82
    (82.0)
    18
    (18.0)
    0
    (0)
    0.595, 0.84
    (0.44–1.60)
    0.577, 0.83
    (0.42–1.62)
    0.577, 0.83
    (0.42–1.62)
     Lung cancer100186
    (93.0)
    14
    (7.0)
    86
    (86.0)
    14
    (14.0)
    0
    (0)
    0.780, 1.10
    (0.55–2.20)
    0.771, 1.11
    (0.54–2.28)
    0.771, 1.11
    (0.54–2.28)
     Gastric cancer100184
    (92.0)
    16
    (8.0)
    84
    (84.0)
    16
    (16.0)
    0
    (0)
    0.892, 0.96
    (0.49–1.86)
    0.887, 0.95
    (0.47–1.91)
    0.887, 0.95
    (0.47–1.91)
     Normal150277
    (92.3)
    23
    (7.7)
    127
    (84.7)
    23
    (15.3)
    0
    (0)
    rs2227478 A/G (1-A, 2-G)
     Liver cancer100163
    (81.5)
    37
    (18.5)
    68
    (68.0)
    27
    (27.0)
    5
    (5.0)
    0.301, 0.78
    (0.48–1.25)
    0.192, 0.38
    (0.09–1.63)
    0.747, 0.91
    (0.51–1.62)
    0.255, 0.42
    (0.09–1.89)
    0.202, 0.39
    (0.09–1.66)
    0.498, 0.83
    (0.48–1.43)
     Lung cancer100165
    (82.5)
    35
    (17.5)
    70
    (70.0)
    25
    (25.0)
    5
    (5.0)
    0.455, 0.83
    (0.51–1.35)
    0.206, 0.39
    (0.09–1.68)
    0.970, 1.01
    (0.56–1.82)
    0.217, 0.39
    (0.08–1.75)
    0.202, 0.39
    (0.09–1.66)
    0.732, 0.91
    (0.52–1.58)
     Gastric cancer100165
    (82.5)
    35
    (17.5)
    69
    (69.0)
    27
    (27.0)
    4
    (4.0)
    0.455, 0.83
    (0.51–1.35)
    0.345, 0.48
    (0.10–2.21)
    0.785, 0.92
    (0.52–1.64)
    0.415, 0.52
    (0.11–2.51)
    0.357, 0.49
    (0.11–2.24)
    0.609, 0.87
    (0.50–1.51)
     Normal150255
    (85.0)
    45
    (15.0)
    108
    (72.0)
    39
    (26.0)
    3
    (2.0)
    rs2227473 C/T (1-C, 2-T)
     Liver cancer100182
    (91.0)
    18
    (9.0)
    83
    (83.0)
    16
    (16.0)
    1
    (1.0)
    0.710, 1.12
    (0.61–2.08)
    0.791, 0.69
    (0.04–11.12)
    0.596, 1.20
    (0.61–2.36)
    0.699, 0.57
    (0.03–9.77)
    0.773, 0.66
    (0.04–10.75)
    0.641, 1.17
    (0.60–2.27)
     Lung cancer100181
    (90.5)
    19
    (9.5)
    82
    (82.0)
    17
    (17.0)
    1
    (1.0)
    0.854, 1.06
    (0.58–1.94)
    0.784, 0.68
    (0.04–10.99)
    0.746, 1.12
    (0.57–2.17)
    0.730, 0.61
    (0.04–10.36)
    0.773, 0.66
    (0.04–10.75)
    0.792, 1.09
    (0.57–2.10)
     Gastric cancer100179
    (89.5)
    21
    (10.5)
    80
    (80.0)
    19
    (19.0)
    1
    (1.0)
    0.856, 0.95
    (0.53–1.71)
    0.771, 0.66
    (0.04–10.72)
    0.937, 0.97
    (0.51–1.86)
    0.788, 0.68
    (0.04–11.53)
    0.773, 0.66
    (0.04–10.75)
    0.897, 0.96
    (0.51–1.81)
     Normal150270
    (90.0)
    30
    (10.0)
    121
    (80.7)
    28
    (18.6)
    1
    (0.7)
    rs2227472 T/C (1-T, 2-C)
     Liver cancer100114
    (57.0)
    86
    (43.0)
    30
    (30.0)
    54
    (54.0)
    16
    (16.0)
    0.557, 1.11
    (0.78–1.60)
    0.473, 1.32
    (0.62–2.83)
    0.854, 0.95
    (0.53–1.69)
    0.349, 1.40
    (0.70–2.80)
    0.356, 1.37
    (0.70–2.66)
    0.910, 1.03
    (0.59–1.80)
     Lung cancer100112
    (56.0)
    88
    (44.0)
    33
    (33.0)
    46
    (46.0)
    21
    (21)
    0.714, 1.07
    (0.75–1.53)
    0.780, 1.11
    (0.54–2.26)
    0.498, 1.22
    (0.68–2.19)
    0.769, 0.91
    (0.47–1.76)
    0.949, 0.98
    (0.53–1.83)
    0.539, 1.19
    (0.69–2.05)
     Gastric cancer100113
    (56.5)
    87
    (43.5)
    32
    (32.0)
    49
    (49.0)
    1919.0)0.633, 1.09
    (0.76–1.57)
    0.646, 1.19
    (0.57–2.46)
    0.717, 1.11
    (0.62–1.99)
    0.853, 1.07
    (0.54–2.09)
    0.747, 1.11
    (0.59–2.10)
    0.653, 1.13
    (0.66–1.96)
     Normal150163
    (54.3)
    137
    (45.7)
    44
    (29.3)
    75
    (50.0)
    31
    (20.7)
      Note. 1The OR (95% CI) and the corresponding P-value were calculated by logistic regression analysis, and adjusted for age, gender, smoking, and drinking status.

    Table S3.  The association between IL22 gene polymorphisms and cancer risk in stage I

    For that rs2227483, rs2227482, rs2227481, rs2227511, rs2227479, and rs2227478 were simultaneously genotyped, we obtained the genotype data of these six SNPs in stage II (1,190 cancer patients and 650 normal controls). Of note, rs2227481, but not other SNPs, was still significantly associated with the risk of liver, lung, and gastric cancer in stage II as well as in stage I+II (Supplementary Table S4, available in www.besjournal.com). As shown in Table 2, the rs2227481 T allele conferred a reduced risk of liver, lung, and gastric cancer at P-values of 0.005, 0.006, and 0.004, respectively, with OR (95% CI) of 0.74 (0.60–0.92), 0.76 (0.62–0.92), and 0.73 (0.59–0.90), respectively, and CT+TT genotypes were associated with a lower risk of gastric cancer than the CC genotype (P = 0.004, OR = 0.68, 95% CI = 0.53–0.89). The pooled data (I+II) revealed an even more significant association between the rs2227481 T allele and lower risk of liver, lung, and gastric cancer, with P-values less than 0.001. Moreover, the rs2227481 T allele genotypes were significantly associated with a lower susceptibility to liver cancer (TT vs. CC, TT vs. CC+CT, and TT+CT vs. CC), lung cancer (TT vs. CC, TT vs. CC+CT, and TT+CT vs. CC), and gastric cancer (TT vs. CC, CT vs. CC, and TT+CT vs. CC).

    GroupsnAllele and genotype (frequency, %)Logistic Regression analysis [P, OR (95% CI)]1
    121112221 vs. 211 vs. 2211 vs. 1212 vs. 2211+12 vs. 2211 vs. 12+22
    rs2227483 A/T (1-A, 2-T) in stage II
     Liver cancer380 401
    (52.8)
    359
    (47.2)
    102
    (26.9)
    197
    (51.8)
    81
    (21.3)
    0.476, 0.94
    (0.78–1.12)
    0.570, 0.90
    (0.63–1.29)
    0.131, 0.80
    (0.59–1.07)
    0.453, 1.13
    (0.82–1.57)
    0.797, 1.04
    (0.77–1.42)
    0.182, 0.83
    (0.62–1.09)
     Lung cancer450475
    (52.8)
    425
    (47.2)
    123
    (27.3)
    229
    (50.9)
    98
    (21.8)
    0.457, 0.94
    (0.79–1.11)
    0.534, 0.90
    (0.64–1.26)
    0.180, 0.82
    (0.62–1.09)
    0.591, 1.09
    (0.80–1.48)
    0.930, 1.01
    (0.76–1.36)
    0.219, 0.85
    (0.65–1.10)
     Gastric cancer360364
    (50.6)
    356
    (49.4)
    90
    (25.0)
    184
    (51.1)
    86
    (23.9)
    0.099, 0.86
    (0.72–1.03)
    0.120, 0.75
    (0.52–1.08)
    0.069, 0.75
    (0.55–1.02)
    0.984, 1.00
    (0.72–1.38)
    0.492, 0.90
    (0.66–1.22)
    0.053, 0.75
    (0.56–1.00)
     Normal controls650707
    (54.4)
    593
    (45.6)
    200
    (30.8)
    307
    (47.2)
    143
    (22.0)
    rs2227483 A/T (1-A, 2-T) in stage I+II
     Liver cancer480510
    (53.1)
    450
    (46.9)
    132
    (27.5)
    246
    (51.2)
    102
    (21.3)
    0.667, 0.97
    (0.82–1.13)
    0.751, 0.95
    (0.69–1.31)
    0.261, 0.86
    (0.66–1.12)
    0.501, 1.11
    (0.83–1.48)
    0.753, 1.05
    (0.79–1.38)
    0.340, 0.89
    (0.69–1.14)
     Lung cancer550586
    (53.3)
    514
    (46.7)
    154
    (28.0)
    278
    (50.5)
    118
    (21.5)
    0.710, 0.97
    (0.83–1.13)
    0.781, 0.96
    (0.70–1.30)
    0.353, 0.89
    (0.69–1.14)
    0.591, 1.08
    (0.82–1.43)
    0.811, 1.03
    (0.79–1.34)
    0.427, 0.91
    (0.71–1.15)
     Gastric cancer460471
    (51.2)
    449
    (48.8)
    119
    (25.9)
    233
    (50.6)
    108
    (23.5)
    0.175, 0.89
    (0.76–1.05)
    0.199, 0.81
    (0.58–1.12)
    0.148, 0.82
    (0.62–1.07)
    0.939, 0.99
    (0.74–1.32)
    0.545, 0.92
    (0.70–1.21)
    0.118, 0.81
    (0.63–1.05)
     Normal controls800864
    (54.0)
    736
    (46.0)
    240
    (30.0)
    384
    (48.0)
    176
    (22.0)
    rs2227511 C/T (1-C, 2-T) in stage II
     Liver cancer380641
    (84.3)
    119
    (15.7)
    271
    (71.3)
    99
    (26.1)
    10
    (2.6)
    0.767, 1.04
    (0.81–1.33)
    0.769, 1.12
    (0.52–2.45)
    0.821, 1.03
    (0.77–1.38)
    0.838, 1.09
    (0.49–2.43)
    0.785, 1.11
    (0.51–2.42)
    0.771, 1.04
    (0.79–1.38)
     Lung cancer450778
    (86.4)
    122
    (13.6)
    337
    (74.9)
    104
    (23.1)
    9
    (2.0)
    0.095, 1.23
    (0.97–1.56)
    0.284, 1.55
    (0.69–3.48)
    0.159, 1.22
    (0.92–1.62)
    0.573, 1.27
    (0.55–2.91)
    0.342, 1.48
    (0.66–3.29)
    0.107, 1.25
    (0.95–1.64)
     Gastric cancer360615
    (85.4)
    105
    (14.6)
    264
    (73.3)
    87
    (24.2)
    9
    (2.5)
    0.352, 1.13
    (0.88–1.46)
    0.634, 1.22
    (0.54–2.73)
    0.371, 1.15
    (0.85–1.55)
    0.888, 1.06
    (0.46–2.44)
    0.695, 1.17
    (0.53–2.62)
    0.333, 1.15
    (0.86–1.54)
     Normal controls6501090
    (83.8)
    210
    (16.2)
    458
    (70.5)
    173
    (26.6)
    19
    (2.9)
    rs2227511 C/T (1-C, 2-T) in stage I+II
     Liver cancer480808
    (84.2)
    152
    (15.8)
    340
    (70.9)
    128
    (26.6)
    12
    (2.5)
    0.911, 1.01
    (0.81–1.26)
    0.884, 1.06
    (0.51–2.17)
    0.924, 1.01
    (0.78–1.31)
    0.914, 1.04
    (0.50–2.19)
    0.891, 1.05
    (0.51–2.16)
    0.899, 1.02
    (0.79–1.30)
     Lung cancer550946
    (86.0)
    154
    (14.0)
    407
    (73.9
    132
    (24.1)
    11
    (2.0)
    0.155, 1.17
    (0.94–1.45)
    0.396, 1.38
    (0.66–2.89)
    0.229, 1.17
    (0.91–1.50)
    0.668, 1.18
    (0.55–2.53)
    0.457, 1.32
    (0.63–2.77)
    0.177, 1.18
    (0.93–1.51)
     Gastric cancer460785
    (85.3)
    135
    (14.7)
    335
    (72.8)
    115
    (25.1)
    10
    (2.2)
    0.376, 1.11
    (0.88–1.39)
    0.571, 1.25
    (0.58–2.68)
    0.436, 1.11
    (0.85–1.45)
    0.772, 1.12
    (0.51–2.47)
    0.619, 1.21
    (0.57–2.60)
    0.379, 1.12
    (0.87–1.45)
     Normal controls8001344
    (84.0)
    256
    (16.0)
    564
    (70.5)
    215
    (26.9)
    21
    (2.6)
    rs2227479 C/T (1-C, 2-T) in stage II
     Liver cancer380722
    (95.0)
    38
    (5.0)
    342
    (90.0)
    38
    (10.0)
    0
    (0)
    0.195, 0.75
    (0.49–1.16)
    0.342, 4.21
    (0.22–81.8)
    0.316, 1.23
    (0.82–1.86)
    0.418, 3.43
    (0.17–68.2)
    0.350, 4.11
    (0.21–79.9)
    0.234, 1.28
    (0.85–1.93)
     Lung cancer450858
    (95.3)
    42
    (4.7)
    408
    (90.7)
    42
    (9.3)
    0
    (0)
    0.319, 0.81
    (0.53–1.23)
    0.286, 5.02
    (0.26–97.5)
    0.156, 1.33
    (0.90–1.98)
    0.382, 3.79
    (0.19–75.1)
    0.295, 4.87
    (0.25–94.5)
    0.107, 1.38
    (0.93–2.05)
     Gastric cancer360670
    (93.1)
    50
    (6.9)
    310
    (86.1)
    50
    (13.9)
    0
    (0)
    0.002, 0.53
    (0.35–0.80)
    0.376, 3.82
    (0.20–74.1)
    0.403, 0.85
    (0.58–1.24)
    0.323, 4.50
    (0.23–89.0)
    0.369, 3.90
    (0.20–75.7)
    0.518, 0.88
    (0.60–1.29)
     Normal controls6501216
    (93.5)
    84
    (6.5)
    569
    (87.5)
    78
    (12.0)
    3
    (0.5)
    rs2227479 C/T (1-C, 2-T) in stage I+II
     Liver cancer480904
    (94.2)
    56
    (5.8)
    424
    (88.3)
    56
    (11.7)
    0
    (0)
    0.392, 1.16
    (0.83–1.62)
    0.338, 4.27
    (0.22–82.8)
    0.596, 1.10
    (0.78–1.56)
    0.371, 3.90
    (0.20–76.8)
    0.341, 4.22
    (0.22–81.8)
    0.485, 1.13
    (0.80–1.60)
     Lung cancer5501044
    (94.9)
    56
    (5.1)
    494
    (89.8)
    56
    (10.2)
    0
    (0)
    0.088, 1.34
    (0.96–1.86)
    0.289, 4.97
    (0.26–96.4)
    0.162, 1.28
    (0.91–1.81)
    0.371, 3.90
    (0.20–76.8)
    0.298, 4.83
    (0.25–93.7)
    0.116, 1.32
    (0.93–1.86)
     Gastric cancer460854
    (92.8)
    66
    (7.2)
    394
    (85.7)
    66
    (14.3)
    0
    (0)
    0.642, 0.93
    (0.68–1.28)
    0.363, 3.97
    (0.20–77.0)
    0.400, 0.87
    (0.62–1.21)
    0.316, 4.59
    (0.23–90.2)
    0.356, 4.04
    (0.21–78.4)
    0.500, 0.89
    (0.64–1.24)
     Normal controls8001493
    (93.3)
    107
    (6.7)
    696
    (87.0)
    101
    (12.6)
    3
    (0.4)
    rs2227478 A/G (1-A, 2-G) in stage II
     Liver cancer380635
    (83.6)
    125
    (16.4)
    262
    (69.0)
    111
    (29.2)
    7
    (1.8)
    0.993, 1.00
    (0.79–1.27)
    0.266, 1.64
    (0.69–3.93)
    0.468, 0.90
    (0.68–1.20)
    0.188, 1.82
    (0.75–4.45)
    0.236, 1.69
    (0.71–4.04)
    0.684, 0.95
    (0.72–1.24)
     Lung cancer450746
    (82.9)
    154
    (17.1)
    304
    (67.5)
    138
    (30.7)
    8
    (1.8)
    0.688, 0.96
    (0.76–1.20)
    0.229, 1.67
    (0.73–3.83)
    0.201, 0.84
    (0.64–1.10)
    0.114, 1.98
    (0.85–4.64)
    0.184, 1.75
    (0.77–4.02)
    0.359, 0.89
    (0.68–1.15)
     Gastric cancer360605
    (84.0)
    115
    (16.0)
    257
    (71.3)
    91
    (25.4)
    12
    (3.3)
    0.775, 1.04
    (0.81–1.33)
    0.867, 0.94
    (0.45–1.95)
    0.621, 1.08
    (0.80–1.45)
    0.723, 0.87
    (0.41–1.86)
    0.824, 0.92
    (0.45–1.91)
    0.680, 1.06
    (0.80–1.41)
     Normal controls6501086
    (83.5)
    214
    (16.5)
    456
    (70.1)
    174
    (26.8)
    20
    (3.1)
    rs2227478 A/G (1-A, 2-G) in stage I+II
     Liver cancer480798
    (83.1)
    162
    (16.9)
    330
    (68.7)
    138
    (28.8)
    12
    (2.5)
    0.650, 0.95
    (0.77–1.18)
    0.752, 1.12
    (0.55–2.28)
    0.431, 0.90
    (0.70–1.16)
    0.561, 1.24
    (0.60–2.58)
    0.691, 1.15
    (0.57–2.34)
    0.509, 0.92
    (0.72–1.18)
     Lung cancer550911
    (82.8)
    189
    (17.2)
    374
    (68.0)
    163
    (29.6)
    13
    (2.4)
    0.495, 0.93
    (0.76–1.14)
    0.651, 1.17
    (0.59–2.35)
    0.246, 0.87
    (0.68–1.10)
    0.403, 1.35
    (0.67–2.75)
    0.567, 1.22
    (0.61–2.44)
    0.327, 0.89
    (0.70–1.13)
     Gastric cancer460770
    (83.7)
    150
    (16.3)
    326
    (70.9)
    118
    (25.6)
    16
    (3.5)
    0.939, 0.99
    (0.80–1.24)
    0.578, 0.83
    (0.43–1.60)
    0.752, 1.04
    (0.80–1.36)
    0.509, 0.80
    (0.41–1.57)
    0.552, 0.82
    (0.43–1.57)
    0.890, 1.02
    (0.79–1.31)
     Normal controls8001341
    (83.8)
    259
    (16.2)
    564
    (70.5)
    213
    (26.6)
    23
    (2.9)
      Note. 1 The OR (95% CI) and the corresponding p-value were calculated by logistic regression analysis, and adjusted for age, gender, smoking, and drinking status.

    Table S4.  The association between IL22 gene polymorphisms and cancer risk in stage II and pooled data (I+II)

    Our two-stage case-control study consistently showed that the rs2227481 C>T polymorphism was significantly associated with a reduced risk of liver, lung, and gastric cancer. The interesting question is why rs2227481 affects individual susceptibility to cancer. In this study, we examined the IL22 mRNA levels in clinical liver, lung, and gastric cancer tissue samples with different rs2227481 genotypes and found that IL22 was upregulated in CC samples compared to combined CT and TT samples (Figure 1AC). These results suggest that maintenance of an inadequate amount of IL22 mRNA may promote the development of liver, lung, and gastric cancers. Evidence from in vitro studies and xenograft models strongly supports our hypothesis. Tumor-infiltrating cells of hepatocellular carcinoma (HCC) are enriched in IL22+ cells, and IL22 expression is positively correlated with the progression and staging of HCC[6]. Similarly, IL22 was found to be elevated in lung cancer tissues compared to matched peritumoral tissues, and overexpression of IL22 protected lung cancer cell lines from serum starvation-induced and chemotherapeutic drug-induced apoptosis[7]. Of note, IL22 is a more unambiguously pro-tumor cytokine in gastric cancer. Gastric cancer patients had higher circulating frequencies of IL22-producing T cells compared to healthy controls, which positively correlated with tumor stage and negatively correlated with patient survival[8].

    Figure 1.  The rs2227481 C>T polymorphism decreases IL22 gene expression by increasing the binding affinity of the transcription repressor POU2F3. Quantitative real-time RT-PCR analysis of in vivo IL22 mRNA levels in 49 liver cancer tissue samples (A), 44 lung cancer tissue samples (B), and 48 gastric cancer tissue samples (C) with different genotypes. (D) Bioinformatics analysis predicted transcription factors for the rs2227481 C>T polymorphism. (E) SPR analysis comparing the binding affinity of HEK293 nuclear extracts or POU2F3 recombinant protein to DNA probes containing either the rs2227481 T or C alleles. (F) ChIP assays using HEK293 cells and one liver cancer tissue sample. The presence of POU2F3 binding to IL22 gene promoter was verified by PCR. (G) A luciferase construct containing either the C or T allele of rs2227481 was co-transfected with pcDNA3.1-basic vector or pcDNA3.1-POU2F3 expression vector in HEK293 cells.

    Next, we used the Alibaba2 software to predict that the rs2227481 C>T polymorphism creates a transcription factor binding site for POU2F3 (Oct-11) (Figure 1D). POU2F3, a member of the POU domain family, acts to both stimulate and repress transcription in a general and cell type-specific mode[9]. Interestingly, the SPR analysis revealed that, compared with the C allele oligonucleotide probe, the T allele oligonucleotide probe had a higher binding affinity to HEK293 nuclear proteins or purified recombinant POU2F3 protein (Figure 1E). Moreover, the ChIP assay results demonstrated that the IL22 promoter fragment with the rs2227481 site was occupied by POU2F3 (Figure 1F). The co-transfection experiment showed that ectopic POU2F3 expression generally decreased the luciferase activities of the plasmids containing the rs2227481 C allele or T allele, and the rs2227481 polymorphism amplified the promoter function disparity (Figure 1G). Taken together, our results demonstrate that POU2F3 acts as a transcription repressor of the IL22 gene, and compared with the C allele, the rs2227481 T allele increases the binding affinity of POU2F3 to the IL22 gene promoter, which finally contributes to the decreased IL22 expression level, thereby reducing cancer susceptibility.

    The present study is the first to demonstrate a significant association between the IL22 rs2227481 C>T polymorphism and a reduced risk of liver, lung, and gastric cancer in a Han Chinese population. Meanwhile, it was also revealed that the IL22 gene rs2227481 C>T polymorphism decreases IL22 expression by increasing the binding affinity of the transcriptional suppressor POU2F3. Our findings emphasize and reinforce the role of IL22 in the carcinogenesis of liver, lung, and gastric cancer, and the results reported here may initiate a novel strategy for the prediction and prevention of liver, lung, and gastric cancer. However, further confirmatory studies with cohort expansion are needed in other ethnic groups and Chinese populations from other regions.

    The authors declare that there are no conflicts of interest.

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