The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution
- Chinese Academy of Sciences, China
- Sun Yat-Sen University Cancer Center, China
- The Third Affiliated Hospital of Kunming Medical University, China
- The First People’s Hospital of Qu Jing City, China
- Chinese PLA General Hospital, China
- Kunming Institute of Zoology, Chinese Academy of Sciences, China
Figures
Figure 1 with 1 supplement
CXCL13 expression in lung cancer.
(A) A PCR array was used to detect the expression of 84 cytokines/chemokines in eight highly polluted region (HPR) lung cancers. (B) The ratios of CXCL13 in tumor samples to their counterpart normal …
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Figure 1—source data 1
Sequences of primers for real-time PCR and ChIP, and siRNA.
- https://doi.org/10.7554/eLife.09419.004
Figure 1—figure supplement 1
Kaplan–Meier estimates of survival of patients with non-small cell lung cancer (NSCLC) according to age, cancer stage, and histology.
https://doi.org/10.7554/eLife.09419.005
Figure 2 with 1 supplement
Benzo(a)pyrene (BaP) induces CXCL13 in vitro and in vivo.
(A) A PCR array analysis of the expression of 84 cytokines/chemokines in 16HBE normal lung epithelial cells treated with 1 μM BaP for 30 days. (B) The cells were treated with BaP at 10 μM for …
Figure 2—figure supplement 1
Benzo(a)pyrene (BaP) induces lung cancer in A/J mice.
(A) Schematic represents the protocols for administration of BaP and/or dexamethasone (DEX) in A/J mice. (B) MicroCT and 3D reconstruction of lung cancer in mice treated with BaP and/or DEX. Av No. …
Figure 3
CXCL13 is a target gene of aryl hydrocarbon receptor (AhR).
(A) The AhR binding site is located at 1.7 kb downstream of the CXCL13 transcription start site (TSS). (B) A chromatin immunoprecipitation (ChIP) assay was performed in BaP-treated or untreated …
Figure 4 with 1 supplement
Cxcl13 and Cxcr5 are critical to benzo(a)pyrene (BaP)-induced lung cancer.
(A) Cxcl13 deficiency mice were treated with BaP, sacrificed 120 days, 180 days or 240 days later, and the tumor nodules in histologic sections were analyzed. See also (Figure 4—figure supplement 1).…
Figure 4—figure supplement 1
Treatment of Cxcl13-/- and Cxcr5-/- mice with benzo(a)pyrene (BaP).
(A) The expression of Cxcl13 in the mice. (B) Schematic represents the protocols for administration of BaP in the mice. (C) The expression of Cxcr5 in the mice.
Figure 5 with 1 supplement
Tumor-associated macrophages in benzo(a)pyrene (BaP)-induced lung cancer.
(A, B) Flow cytometry analysis of Cd68+ macrophages in BaP-induced tumors. A representative gating is shown. The numbers indicate the Cd68+ cells in the quadrant expressed as the percentage of the …
Figure 5—figure supplement 1
Analysis of B cells and T cells in benzo(a)pyrene (BaP)-induced lung cancer.
(A) The expression of Cd19 in Cd45+ leukocytes sorted from lung cancer tumor samples was analyzed by flow cytometry. (B) The expression of Cd4 was analyzed in Cd45+ leukocytes by flow cytometry.
Figure 6 with 1 supplement
Identification of macrophage-secreted SPP1 as a downstream effector of CXCL13.
(A) The pathway analysis of CXCL13 associated genes. The data from the microarray data sets of the eight highly polluted region (HPR) lung cancers are shown. See also Figure 6—source data 1. (B) …
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Figure 6—source data 1
CXCL13-associated genes in lung cancer.
- https://doi.org/10.7554/eLife.09419.017
Figure 6—figure supplement 1
Activation of β-catenin and epithelial mesenchymal transition (EMT) in benzo(a)pyrene (BaP)-induced lung cancer.
(A) The expression of indicated genes in lung tissues from A/J mice treated with BaP and/or dexamethasone (DEX) was detected by real-time PCR. (B) Western blot analyses of lysates of lung tissues …
Tables
Table 1
Baseline demographic characteristics of the 201 patients who underwent CXCL13 analyses.
| Characteristics | Total | Highly polluted region (HPR) | Control region (CR) | p values (HPR vs CR) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Case, n | CXCL13 high, n (%) | p values | Case, n | CXCL13 high, n (%) | p values | Case, n | CXCL13 high, n (%) | p values | ||
| Total | 201 | 134 (66.7) | 70 | 63 (90) | 131 | 71 (54.2) | 0.0000003 | |||
| G: Male | 134 | 88 (65.7) | 0.67 | 47 | 41 (87.2) | 0.27 | 87 | 47 (54) | 0.95 | 0.0001 |
| Female | 67 | 46 (68.7) | 23 | 22 (95.7) | 44 | 24 (54.5) | 0.0006 | |||
| A: <65 y | 140 | 98 (70) | 0.21 | 56 | 51 (91.1) | 0.55 | 84 | 47 (56) | 0.7 | 0.000009 |
| ≥65 y | 56 | 34 (60.7) | 14 | 12 (85.7) | 42 | 22 (52.4) | 0.03 | |||
| Unknown | 5 | 2 (40) | 5 | 2 (40) | ||||||
| S: Smoker | 107 | 75 (70.1) | 0.18 | 36 | 31 (86.1) | 0.17 | 71 | 44 (62) | 0.04 | 0.01 |
| Non-smoker | 87 | 53 (60.9) | 27 | 26 (96.3) | 60 | 27 (45) | 0.000006 | |||
| Unknown | 7 | 6 (85.7) | 7 | 6 (85.7) | ||||||
| H: Adenocarcinoma (AD) | 131 | 91 (69.5) | 0.45 | 48 | 44 (91.7) | 0.37 | 83 | 47 (56.6) | 0.84 | 0.00003 |
| Squamous cell carcinoma (SCC) | 61 | 39 (63.9) | 19 | 16 (84.2) | 42 | 23 (54.8) | 0.03 | |||
| Others | 9 | 4 (44.4) | 3 | 3 (100) | 6 | 1 (16.7) | ||||
| Tumor node metastasis (TNM): I | 88 | 51 (58) | 0.007 | 29 | 23 (79.3) | 0.02 | 59 | 28 (47.5) | 0.05 | 0.004 |
| II | 27 | 17 (63) | 9 | 8 (88.9) | 18 | 9 (50) | 0.005 | |||
| III | 58 | 43 (74.1) | 17 | 17 (100) | 41 | 26 (63.4) | 0.004 | |||
| IV | 22 | 19 (86.4) | 11 | 11 (100) | 11 | 8 (72.7) | 0.06 | |||
| Unknown | 6 | 4 (66.7) | 4 | 4 (100) | 2 | 0 (0) | ||||
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G, gender; A, age; S, smoke; H, histology.
Table 2
Multivariate logistic analyses of the association between CXCL13 high expression and clinical characteristics.
| Highly polluted region (HPR) patients, n=70 | |||
| Variable | Odds ratio | 95.0% confidence interval | P value |
| Age | 1.483 | 0.177–12.452 | 0.716 |
| Gender | 4.711 | 0.488–45.51 | 0.18 |
| Smoking | 0.652 | 0.115–3.682 | 0.628 |
| Histology | 0.37 | 0.069–1.992 | 0.247 |
| TNM stage | 3.092 | 0.765–12.502 | 0.113 |
| Control region (CR) patients, n=131 | |||
| Variable | Odds ratio | 95.0% confidence interval | P value |
| Age | 0.914 | 0.455–1.832 | 0.799 |
| Gender | 2.15 | 0.772–5.993 | 0.143 |
| Smoking | 0.513 | 0.251–1.052 | 0.06 |
| Histology | 1.148 | 0.569–2.313 | 0.7 |
| TNM stage | 2.355 | 1.157–4.793 | 0.018 |
| Total (HPR and CR patients), n=201 | |||
| Variable | Odds ratio | 95.0% confidence interval | P value |
| Region | 7.908 | 3.272–19.114 | 4.6×10-6 |
| Age | 0.964 | 0.5–1.861 | 0.914 |
| Gender | 2.254 | 0.897–5.662 | 0.084 |
| Smoking | 0.394 | 0.168–0.925 | 0.032 |
| Histology | 0.996 | 0.52–1.907 | 0.99 |
| TNM stage | 2.707 | 1.401–5.232 | 0.003 |
Table 3
Baseline demographic characteristics of 54 control region (CR) lung cancer patients whose survival information was available.
| Characteristics | Case, n | CXCL13-high, n (%) | P* Value |
|---|---|---|---|
| Total | 54 | 25 (46.3) | |
| Gender | |||
| Male | 38 | 16 (42.1) | 0.34 |
| Female | 16 | 9 (56.3) | |
| Smoking | |||
| Smoker | 33 | 16 (48.5) | 0.69 |
| Non-smoker | 21 | 9 (42.9) | |
| Age, years | 0.72 | ||
| <65 | 38 | 17 (44.7) | |
| ≥65 | 16 | 8 (50) | |
| Histology | |||
| Adenocarcinoma | 32 | 15 (46.9) | 0.83 |
| squamous cell carcinoma | 18 | 9 (50) | |
| small cell lung cancer | 1 | 0 (0) | |
| Others | 3 | 1 (33.3) | |
| TNM stage | 0.65 | ||
| I | 26 | 12 (46.2) | |
| II | 6 | 2 (33.3) | |
| III | 18 | 9 (50) | |
| IV | 4 | 2 (50) |
