Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Patient and Tumor Characteristics
2.2. Results of Immunohistochemical Staining
2.3. Interpretation of the Relationship between EMT-TFs and Histone Lysine Modification
2.4. Univariate Analysis of Factors Predicting Survival
2.5. Multivariate Analysis of Factors Predicting Survival
3. Discussion
4. Materials and Methods
4.1. Sample Collection
4.2. Clinical and Radiological Data
4.3. Immunohistochemical Staining and Its Interpretation
4.4. Quantitative Reverse Transcription Polymerase Chain Reaction for mRNA
4.5. Survival Analysis and Statistical Analysis
4.6. Ethical Statement
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Clinical Features | Number (%) | |
---|---|---|
Gender | Male | 30 (65.2%) |
Female | 16 (34.8%) | |
Mean Age (Year) | 60.2 (42.6–84.5) | |
KPS | ≥70 | 34 (73.9%) |
<70 | 12 (26.1%) | |
Clinical T Stage | T1 | 2 (4.3%) |
T2 | 6 (13.0%) | |
T3 | 20 (43.6%) | |
T4 | 18 (39.1%) | |
Clinical N Stage | N0 | 0 (0.0%) |
N1 | 2 (4.3%) | |
N2 | 32 (69.6%) | |
N3 | 12 (26.1%) | |
Timing of Brain Metastasis | Synchronous | 18 (39.1%) |
Metachronous | 28 (60.9%) | |
Number of Brain Metastasis | 1 | 32 (69.6%) |
2–3 | 10 (21.7%) | |
≥4 | 4 (8.7%) | |
Metastatic Site | Brain | 46 (100.0%) |
Adrenal Gland | 24 (52.2%) | |
Liver | 6 (13.0%) | |
Bone | 18 (39.1%) | |
Opposite Lung | 28 (60.9%) | |
Others | 8 (17.4%) | |
Treatment after Brain Metastasis | Cytotoxic Chemotherapy | 10 (21.7%) |
Target Therapy | 34 (73.7%) | |
Immunotherapy | 12 (26.1%) | |
Radiotherapy | 40 (87.0%) | |
Combination | 42 (91.3%) | |
Survival after Diagnosis of Lung Adenocarcinoma (95% CI) | 19.5 (13.2–25.3) | |
Survival after Brain Metastasis (95% CI) | 5.8 (1.4–8.6) |
Factors | Lung Adenocarcinoma | Brain Metastasis | p Value |
---|---|---|---|
Epithelial Markers | |||
E-cadherin | 24.6% | 12.6% | 0.037 |
Occludins | 37.4% | 28.9% | 0.254 |
Desmoplakin | 15.6% | 2.3% | 0.007 |
α-catenin | 41.3% | 28.3% | 0.042 |
β-catenin | 38.6% | 16.9% | 0.029 |
Type IV collagen | 52.3% | 45.3% | 0.384 |
Mesenchymal Markers | |||
N-cadherin | 20.6% | 43.2% | 0.028 |
Vimentin | 15.3% | 51.6% | 0.004 |
Fibronectin | 7.6% | 39.4% | 0.002 |
α5β1 integrin | 16.3% | 18.9% | 0.843 |
αγβ6 integrin | 22.6% | 27.4% | 0.726 |
Type I collagen | 37.8% | 45.2% | 0.662 |
Transcription Factors | |||
Snail | 38.6% | 28.7% | 0.154 |
Slug | 15.6% | 42.6% | 0.005 |
Twist | 23.6% | 45.9% | 0.010 |
ZEB1 | 15.0% | 55.9% | 0.002 |
FOXC2 | 35.6% | 47.2% | 0.527 |
Histone Methyltransferase | |||
MLL4 (H3K4) | 13.9% | 46.9% | 0.018 |
RIZ (H3K9) | 38.6% | 33.3% | 0.561 |
EZH2 (H3K27) | 25.6% | 8.6% | 0.046 |
NSD2 (H3K36) | 20.5% | 22.8% | 0.837 |
Histone Demethylase | |||
LSD1 (H3K4) | 42.3% | 28.9% | 0.170 |
JMJD1 (H3K9) | 20.5% | 24.3% | 0.642 |
UTX (H3K27) | 32.4% | 70.6% | 0.003 |
JMJD5 (H3K36) | 15.6% | 22.1% | 0.389 |
Factors | Lung Adenocarcinoma | Brain Metastasis | ||||
---|---|---|---|---|---|---|
Mean% of IHC Staining Nuclei (%, ± SD) | AUC in ROC Curve | Cutoff Value (%) | Mean% of IHC Staining Nuclei (%, ± SD) | AUC in ROC Curve | Cutoff Value (%) | |
Epithelial Markers | ||||||
E-cadherin | 24.6 ± 8.6 | 0.58 | 25 | 12.6 ± 7.2 | 0.62 | 14 |
Occludins | 37.4 ± 18.9 | 0.64 | 35 | 28.9 ± 13.5 | 0.64 | 30 |
Desmoplakin | 15.6 ± 7.9 | 0.71 | 15 | 2.3 ± 1.2 | 0.72 | 2 |
α-catenin | 41.3 ± 24.0 | 0.68 | 40 | 28.3 ±10.8 | 0.70 | 28 |
β-catenin | 38.6 ± 17.5 | 0.72 | 37 | 16.9 ± 8.6 | 0.77 | 15 |
Type IV Collagen | 52.3 ± 31.9 | 0.62 | 50 | 45.3 ± 22.9 | 0.72 | 45 |
Mesenchymal Markers | ||||||
N-cadherin | 20.6 ± 11.2 | 0.71 | 20 | 43.2 ±20.7 | 0.78 | 41 |
Vimentin | 15.3 ± 8.8 | 0.69 | 15 | 51.6 ± 34.5 | 0.70 | 50 |
Fibronectin | 7.6 ± 4.6 | 0.60 | 7 | 39.4 ± 15.6 | 0.75 | 38 |
α5β1 integrin | 16.3 ± 7.0 | 0.73 | 15 | 18.9 ± 8.6 | 0.67 | 17 |
αγβ6 integrin | 22.6 ± 10.9 | 0.79 | 21 | 27.4 ± 10.5 | 0.71 | 25 |
Type I collagen | 37.8 ± 20.1 | 0.64 | 36 | 45.2 ± 22.7 | 0.68 | 45 |
Transcription Factors | ||||||
Snail | 38.6 ± 16.4 | 0.84 | 35 | 28.7 ± 13.0 | 0.72 | 27 |
Slug | 15.6 ± 4.8 | 0.75 | 15 | 42.6 ± 19.4 | 0.58 | 40 |
Twist | 23.6 ± 10.8 | 0.72 | 22 | 45.9 ± 26.8 | 0.68 | 45 |
ZEB1 | 15.0 ± 6.9 | 0.68 | 14 | 55.9 ± 31.3 | 0.61 | 54 |
FOXC2 | 35.6 ± 17.3 | 0.67 | 36 | 47.2 ± 15.9 | 0.63 | 46 |
Histone Methyltransferase | ||||||
MLL4(H3K4) | 13.9 ± 6.3 | 0.75 | 14 | 46.9 ± 20.4 | 0.73 | 43 |
RIZ(H3K9) | 38.6 ± 14.6 | 0.80 | 37 | 33.3 ± 18.1 | 0.68 | 31 |
EZH2(H3K27) | 25.6 ± 15.4 | 0.67 | 25 | 8.6 ± 4.2 | 0.59 | 10 |
NSD2(H3K36) | 20.5 ± 9.5 | 0.74 | 20 | 22.8 ± 9.8 | 0.62 | 22 |
Histone Demethylase | ||||||
LSD1(H3K4) | 42.3 ± 18.6 | 0.65 | 41 | 28.9 ± 11.3 | 0.64 | 27 |
JMJD1(H3K9) | 20.5 ± 8.2 | 0.76 | 20 | 24.3 ± 9.2 | 0.70 | 25 |
UTX(H3K27) | 32.4 ± 15.0 | 0.84 | 34 | 70.6 ± 27.3 | 0.69 | 70 |
JMJD5(H3K36) | 15.6 ± 6.7 | 0.67 | 16 | 22.1 ± 7.6 | 0.75 | 22 |
Immunoreactivity | Overall Survival (Mean, Months) | Hazard Ratio | 95% CI | p Value | |
---|---|---|---|---|---|
E-cadherin | Low | 11.3 | 1.00 | 2.46–6.18 | 0.002 |
High | 27.0 | 4.32 | |||
Occludins | Low | 18.6 | 1.00 | 0.88–1.64 | 0.724 |
High | 20.3 | 1.26 | |||
Desmoplakin | Low | 13.7 | 1.00 | 2.22–5.67 | 0.014 |
High | 24.8 | 3.94 | |||
α-catenin | Low | 17.0 | 1.00 | 0.96–3.34 | 0.062 |
High | 21.8 | 2.15 | |||
β-catenin | Low | 19.2 | 1.00 | 0.64–1.62 | 0.884 |
High | 19.8 | 1.13 | |||
Type IV collagen | Low | 20.4 | 1.00 | 0.47–1.46 | 0.903 |
High | 18.7 | 0.97 | |||
N-cadherin | Low | 21.6 | 1.00 | 0.13–1.03 | 0.067 |
High | 17.6 | 0.58 | |||
Vimentin | Low | 23.1 | 1.00 | 0.25–0.67 | 0.034 |
High | 16.2 | 0.46 | |||
Fibronectin | Low | 20.8 | 1.00 | 0.55–1.09 | 0.073 |
High | 18.3 | 0.82 | |||
α5β1 integrin | Low | 19.8 | 1.00 | 0.74–1.22 | 0.325 |
High | 19.2 | 0.98 | |||
αγβ6 integrin | Low | 21.3 | 1.00 | 0.26–1.08 | 0.091 |
High | 17.9 | 0.67 | |||
Type I collagen | Low | 22.0 | 1.00 | 0.18–1.09 | 0.069 |
High | 17.2 | 0.63 | |||
Snail | Low | 21.6 | 1.00 | 0.47–1.15 | 0.084 |
High | 17.6 | 0.81 | |||
Slug | Low | 22.9 | 1.00 | 0.42–0.95 | 0.042 |
High | 16.4 | 0.69 | |||
Twist | Low | 25.1 | 1.00 | 0.24–0.83 | 0.007 |
High | 14.4 | 0.53 | |||
ZEB1 | Low | 24.3 | 1.00 | 0.31–0.88 | 0.010 |
High | 15.1 | 0.59 | |||
FOXC2 | Low | 22.0 | 1.00 | 0.27–1.26 | 0.206 |
High | 17.2 | 0.76 |
Immunoreactivity | Overall Survival (Mean, Months) | Hazard Ratio | 95% CI | p Value | |
---|---|---|---|---|---|
E-cadherin | Low | 20.3 | 1.00 | 0.54–1.24 | 0.416 |
High | 18.7 | 0.84 | |||
Occludins | Low | 18.6 | 1.00 | 0.78–2.26 | 0.524 |
High | 20.3 | 1.52 | |||
Desmoplakin | Low | 21.6 | 1.00 | 0.36–1.14 | 0.231 |
High | 17.6 | 0.75 | |||
α-catenin | Low | 20.4 | 1.00 | 0.64–1.18 | 0.448 |
High | 18.7 | 0.91 | |||
β-catenin | Low | 19.0 | 1.00 | 0.54–1.90 | 0.643 |
High | 19.9 | 1.22 | |||
Type IV collagen | Low | 17.2 | 1.00 | 0.93–4.77 | 0.152 |
High | 21.6 | 2.85 | |||
N-cadherin | Low | 22.3 | 1.00 | 0.15–0.93 | 0.027 |
High | 16.9 | 0.54 | |||
Vimentin | Low | 25.4 | 1.00 | 0.10–0.84 | 0.004 |
High | 14.1 | 0.47 | |||
Fibronectin | Low | 23.4 | 1.00 | 0.25–0.88 | 0.020 |
High | 15.9 | 0.57 | |||
α5β1 integrin | Low | 21.7 | 1.00 | 0.34–1.08 | 0.065 |
High | 17.5 | 0.71 | |||
αγβ6 integrin | Low | 22.1 | 1.00 | 0.42–1.17 | 0.118 |
High | 17.1 | 0.79 | |||
Type I collagen | Low | 21.5 | 1.00 | 0.48–1.21 | 0.251 |
High | 17.7 | 0.84 | |||
Snail | Low | 23.5 | 1.00 | 0.25–0.92 | 0.014 |
High | 15.8 | 0.58 | |||
Slug | Low | 27.6 | 1.00 | 0.18–0.65 | 0.009 |
High | 12.1 | 0.41 | |||
Twist | Low | 28.4 | 1.00 | 0.08–0.44 | 0.005 |
High | 11.4 | 0.26 | |||
ZEB1 | Low | 32.1 | 1.00 | 0.05–0.34 | <0.001 |
High | 8.1 | 0.19 | |||
FOXC2 | Low | 24.6 | 1.00 | 0.35–0.53 | 0.012 |
High | 14.8 | 0.44 |
Factors | Hazard Ratio | 95% CI | p Value |
---|---|---|---|
Age (<60 years vs. ≥60 years) | 1.820 | 0.852–2.788 | 0.275 |
KPS (≥70 vs. <70) | 2.772 | 1.194–4.779 | 0.042 |
Number of BM (≥4 vs. <4) | 1.542 | 0.765–2.319 | 0.482 |
Timing of BM (≥2 months vs. <2 months) | 1.286 | 0.684–1.888 | 0.671 |
Clinical T Stage (4 vs. 1–3) | 2.235 | 0.917–3.553 | 0.106 |
Clinical N Stage (4 vs. 1–3) | 2.418 | 0.943–3.893 | 0.062 |
E-cadherin of lung (high vs. low) | 2.756 | 1.347–4.165 | 0.044 |
Desmoplakin of lung (high vs. low) | 1.368 | 0.886–1.850 | 0.442 |
Vimentin of lung (low vs. high) | 2.627 | 1.158–4.096 | 0.048 |
Slug of lung (low vs. high) | 3.241 | 1.873–4.609 | 0.020 |
Twist of lung (low vs. high) | 2.976 | 1.882–4.071 | 0.027 |
ZEB1 of lung (low vs. high) | 2.480 | 0.935–4.024 | 0.056 |
N-cadherin of brain (low vs. high) | 3.054 | 1.992–4.116 | 0.018 |
Vimentin of brain (low vs. high) | 4.274 | 2.607–5.941 | 0.002 |
Fibronectin of brain (low vs. high) | 1.942 | 0.907–2.978 | 0.152 |
Snail of brain (low vs. high) | 1.802 | 0.806–2.798 | 0.199 |
Slug of brain (low vs. high) | 3.547 | 2.844–4.251 | 0.011 |
Twist of the brain (low vs. high) | 3.913 | 3.007–4.819 | 0.006 |
ZEB1 of brain (low vs. high) | 2.945 | 1.523–4.367 | 0.038 |
FOXC2 of brain (low vs. high) | 2.004 | 0.897–3.111 | 0.086 |
MLL4 of brain (low vs. high) | 1.252 | 0.647–1.857 | 0.574 |
EZH2 of brain (high vs. low) | 1.674 | 0.579–2.769 | 0.306 |
UTX of brain (low vs. high) | 1.842 | 0.806–2.878 | 0.155 |
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Lee, Y.M.; Kim, S.H.; Kim, M.S.; Kim, D.C.; Lee, E.H.; Lee, J.S.; Lee, S.-H.; Kim, Y.Z. Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain. Cancers 2020, 12, 3632. https://doi.org/10.3390/cancers12123632
Lee YM, Kim SH, Kim MS, Kim DC, Lee EH, Lee JS, Lee S-H, Kim YZ. Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain. Cancers. 2020; 12(12):3632. https://doi.org/10.3390/cancers12123632
Chicago/Turabian StyleLee, Young Min, Seok Hyun Kim, Minseok S. Kim, Dae Cheol Kim, Eun Hee Lee, Ju Suk Lee, Sung-Hun Lee, and Young Zoon Kim. 2020. "Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain" Cancers 12, no. 12: 3632. https://doi.org/10.3390/cancers12123632