Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models
Abstract
:1. Introduction
2. Results
2.1. Evaluation of the Molecular Profile of EAC and BE in Clinical Samples According to the GSE Datasets
2.2. Molecular Profile of Normal Esophageal Epithelium, BE and EAC Representing Cell Lines
2.3. Cells Viability and the Resistance to Various Concentrations of BM on Subsequent Stages of Esophageal Metaplasia Development
2.4. The Effect of Chronic GERD on the Molecular Profile of Cells Representing Subsequent Stages of Esophageal Metaplasia and Esophageal Adenocarcinoma
3. Discussion
4. Materials and Methods
4.1. Evaluation of EAC and BE Gene Expression Profiles in Clinical Samples Based on the GSE Database
4.2. Cell Cultures
4.3. Cell Viability Assay
4.4. Experimental Model of GERD Induced by Chronic Treatment with BM
4.5. Determination of Molecular Profile by Real-Time PCR
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Database No. GSE1420 Tissue Type: Adenocarcinoma (EAC) | Adenocarcinoma (n = 8) vs. Normal Esophageal Epithelium (n = 8) | Log Fc > 1 Log Fc < −1 | Adenocarcinoma (n = 8) vs. Barrett’s Esophagus (n = 8) | Log Fc > 1 Log Fc < −1 | |||
---|---|---|---|---|---|---|---|
Gene Symbol | Gene ID | p-Value | logFc | p-Value | logFc | ||
FZD5 | 206136_at | 8.69 × 10−4 * | 1.8969691 | ↑ | 0.1408974 | 0.84570984 | ↔ |
IFNGR1 | 202727_s_at | 4.46 × 10−4 * | 1.0490922 | ↑ | 0.2911745 | 0.34897639 | ↔ |
IL1A | 20118_s_at | 4.37 × 10−3 * | −2.1008288 | ↓ | 0.0007048 * | −2.10433414 | ↓ |
IL1B | 39402_at | 4.50 × 10−2 * | 1.1091709 | ↑ | 0.358504 | −0.54312669 | ↔ |
IL1R1 | 215561_s_at | 4.35 × 10−2 * | −0.7384266 | ↔ | 0.7571835 | −0.13554952 | ↔ |
IL1RN | 216244_at | 1.43 × 10−3 * | −4.8525406 | ↓ | 0.0013027 * | −3.99004005 | ↓ |
KRT4 | 213240_s_at | 1.43 × 10−3 * | −5.7005044 | ↓ | 0.0001973 * | −6.2440119 | ↓ |
KRT8 | 209008_x_at | 2.17 × 10−7 * | 3.1887753 | ↑ | 0.3836391 | 0.50810515 | ↔ |
KRT15 | 204734_at | 2.24 ×10−3 * | −5.72458 | ↓ | 0.0002355 * | −5.39716256 | ↓ |
KRT18 | 201596_x_at | 2.73 × 10−4 * | 2.2219105 | ↑ | 0.3513037 | 0.29363309 | ↔ |
NFKBIL1 | 209973_at | 1.80 × 10−3 * | −1.3808285 | ↓ | 0.4237075 | −0.31419507 | ↔ |
PTGS1 | 205127_at | 5.19 × 10−3 * | −1.8055694 | ↓ | 0.0407174 * | −1.06765124 | ↓ |
PTGS2 | 204748_at | 5.04 × 10−2 * | 1.4108709 | ↑ | 0.7493048 | −0.25959637 | ↔ |
SOCS3 | 206359_at | 2.16 × 10−4 * | 2.5970676 | ↑ | 0.9710285 | −0.01769524 | ↔ |
SOX4 | 201416_at | 1.96 × 10−4 * | 1.6060934 | ↑ | 0.009393 * | 0.77714721 | ↔ |
SOX9 | 202935_s_at | 8.77 × 10−4 * | 2.3750816 | ↑ | 0.2308111 | 0.67648591 | ↔ |
SOX15 | 206122_at | 6.63 × 10−5 * | −3.6497616 | ↓ | 0.0087003 * | −2.52633017 | ↓ |
TIMP1 | 201666_at | 3.71 × 10−5 * | 2.4187493 | ↑ | 0.0535691 | 0.85285424 | ↔ |
TMEM2 | 218113_at | 7.98 × 10−6 * | 2.0502962 | ↑ | 0.6940281 | 0.11423942 | ↔ |
TNFRSF10B | 209294_x_at | 2.17 × 10−3 * | 1.9376771 | ↑ | 0.4609293 | 0.32614131 | ↔ |
Gene Symbol | Gene ID | Database No. GSE1420 (n = 16) Target Tissue: Barrett’s Esophagus | Database No. GSE13083 (n = 14) Target Tissue: Barrett’s Esophagus | Database No. GSE34619 (n = 18) Target Tissue: Barrett’s Esophagus | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Barrett’s Esophagus (n = 8) vs. Normal Esophageal Epithelium (n = 8) | Log Fc > 1Log Fc < −1 | Barrett’s Esophagus (n = 7) vs. Normal Esophageal Epithelium (n = 7) | Log Fc > 1Log Fc < −1 | Barrett’s Esophagus (n = 10) vs. Normal Esophageal Epithelium (n = 8) | Log Fc > 1 Log Fc < −1 | ||||||
p-Value | logFc | p-Value | logFc | Gene ID | p-Value | logFc | |||||
FZD5 | 206136_at | 1.58 × 10−2 * | 1.0512592 | ↑ | 7.17 × 10−1 | −0.00823 | ↔ | 8058498 | 7.86 × 10−11 * | 1.9280655 | ↑ |
IFNGR1 | 202727_s_at | 2.44 × 10−2 | 0.7001158 | ↔ | 2.10 × 10−5 * | 1.5619957 | ↑ | 8129861 | 6.36 × 10−2 | 0.406583 | ↔ |
IL1A | 210118_s_at | 9.96 × 10−1 | 0.0035053 | ↔ | 2.59 × 10−4 * | −2.7528729 | ↓ | 8054712 | 3.90 × 10−2 * | −3.6254277 | ↓ |
IL1B | 39402_at | 1.55 × 10−5 * | 2.9966785 | ↑ | 3.31 × 10−1 | −0.0601271 | ↔ | 8054722 | 1.15× 10−2 * | 1.0997835 | ↑ |
IL1R1 | 215561_s_at | 3.77 × 10−1 | −0.8625006 | ↔ | 6.81 × 10−2 | −0.1481829 | ↔ | 8043995 | 1.69× 10−1 | −0.2684032 | ↔ |
IL1RN | 216244_at | 9.25 × 10−2 | −0.6028771 | ↔ | 7.82 × 10−7 * | −3.95939 | ↓ | 8044574 | 1.65 × 10−10 * | −3.9754035 | ↓ |
KRT15 | 204734_at | 8.15 × 10−1 | −0.3274174 | ↔ | 1.79 × 10−4 * | −6.05938 | ↓ | 8015337 | 2.13 × 10−12 * | −4.686177 | ↓ |
KRT18 | 201596_x_at | 1.95 × 10−3 * | 1.9282774 | ↑ | 9.62 × 10−8 * | 3.4490243 | ↑ | 8154725 | 1.04 × 10−7 * | 2.024285 | ↑ |
KRT4 | 213240_s_at | 5.13 × 10−1 | 0.5435075 | ↔ | 1.08 × 10−2 * | −4.6401743 | ↓ | 7963534 | 1.48 × 10−6 * | −5.428193 | ↓ |
KRT8 | 209008_x_at | 2.25 × 10−4 * | 2.6806701 | ↑ | 4.59 × 10−12 * | 6.4172871 | ↑ | 7963567 | 1.46 × 10−13 * | 4.0091987 | ↑ |
NFKBIL1 | 209973_at | 1.29 × 10−4 * | −1.0666335 | ↓ | 2.51 × 10−3 * | −0.1449743 | ↔ | 8118127 | 7.68 × 10−1 | −0.0326435 | ↔ |
8177967 | |||||||||||
8179249 | |||||||||||
PTGS1 | 205127_at | 9.30 × 10−2 | −0.7379182 | ↔ | 3.03 × 10−2 * | −0.2672243 | ↔ | 8157650 | 1.20 × 10−6 * | −1.233037 | ↓ |
PTGS2 | 204748_at | 3.44 × 10−2 * | 1.6704673 | ↑ | 1.55 × 10−1 | −0.0942814 | ↔ | 7922976 | 1.57 × 10−1 | 0.7297863 | ↔ |
SOCS3 | 206359_at | 4.66 × 10−4 * | 2.6147628 | ↑ | 1.16 × 10−1 | −0.2276743 | ↔ | 8018864 | 1.11× 10−1 | 0.2751112 | ↔ |
SOX15 | 206122_at | 8.35 × 10−2 | −1.1234314 | ↓ | 1.48 × 10−5 * | −2.3811471 | ↓ | 8012220 | 3.32 × 10−10 * | −1.168799 | ↓ |
SOX4 | 201416_at | 1.31 × 10−2 | 0.8289462 | ↔ | 1.88 × 10−6 * | 3.2003314 | ↑ | 8117165 | 1.77 × 10−5 | 0.74846 | ↔ |
SOX9 | 202935_s_at | 3.00 × 10−3 * | 1.6985957 | ↑ | 5.01 × 10−4 * | 2.4066814 | ↑ | 8009517 | 1.83 × 10−4 | 0.7532475 | ↔ |
TIMP1 | 201666_at | 1.03 × 10−2 * | 1.565895 | ↑ | 9.31× 10−8 * | 5.4677657 | ↑ | 8167185 | 2.86× 10−5 * | 1.8116638 | ↑ |
TMEM2 | 218113_at | 1.10 × 10−5 * | 1.9360567 | ↑ | 5.36 × 10−8 * | 3.5432943 | ↑ | 8161701 | 8.05 × 10−13 * | 3.0865858 | ↑ |
TNFRSF10B | 209294_x_at | 2.89 × 10−3 * | 1.6115358 | ↑ | 1.64 × 10−1 | 0.2274829 | ↔ | 8149733 | 1.66 × 10−11 * | 1.6029245 | ↑ |
No | Function | Gene |
---|---|---|
I | Inflammatory response pathways | IL1A, IL1B, IL1RN, IL1R1, PTGS1, PTGS2, NFKBIL, SOCS3 [38,39,40,41,42,43,44,45,61,62,65,66,67] |
II | Epithelial/squamous origin | KRT gene family: KRT4, KRT8, KRT15, KRT18 [56,57,58,59,60,68,69] |
III | Wnt/β-catenin signaling pathway | SOX4, SOX9, SOX15, FZD5, TMEM2 [46,47,48,49,50,51,52,53,54,55,70] |
IV | Cell proliferation and/or apoptosis | IFNGR1,TIMP1, TNFRSF10B [63,64,71] |
Gene Symbol | Clinical: | Experimental: | Experimental: |
---|---|---|---|
EAC vs. Normal Epithelium | OE33 vs. EPC2 | OE19 vs. EPC2 | |
FZD5 | ↑ | ↑ | ↑ |
IFNGR1 | ↑ | ↓ | ↓ |
IL1A | ↓ | ↓ | ↓ |
IL1B | ↑ | ↓ | ↓ |
IL1R1 | ↔ | ↓ | ↓ |
IL1RN | ↓ | ↓ | ↓ |
KRT15 | ↓ | ↓ | ↓ |
KRT18 | ↑ | ↑ | ↑ |
KRT4 | ↓ | ↓ | ↓ |
KRT8 | ↑ | ↑ | ↑ |
NFKBIL1 | ↓ | ↓ | ↓ |
PTGS1 | ↓ | ↓ | ↓ |
PTGS2 | ↑ | ↑ | ↓ |
SOCS3 | ↑ | ↑ | ↓ |
SOX15 | ↓ | ↓ | ↓ |
SOX4 | ↑ | ↑ | ↑ |
SOX9 | ↑ | ↑ | ↑ |
TIMP1 | ↑ | ↔ | ↔ |
TMEM2 | ↑ | ↑ | ↑ |
TNFRSF10B | ↑ | ↔ | ↔ |
Alternations in Gene Expression—A Summary | |||||||
---|---|---|---|---|---|---|---|
Functional Group | Gene Symbol | Human-Derived EAC vs. BE (GSE1420 Database) | Untreated Wild Type Cell Lines | BAR-T upon 250 μM BM Treatment | OE33 upon 250 μM BM Treatment | OE19 upon 250 μM BM Treatment | |
OE33 vs. BAR-T | OE19 vs. BAR-T | ||||||
group I | IL1A | ↓ | ↓ | ↓ | ↔ | ↑ | ↓ |
group I | IL1B | ↔ | ↓ | ↓ | ↔ | ↑ | ↑ |
IL1R1 | ↔ | ↓ | ↑ | ↔ | ↔ | ↔ | |
IL1RN | ↓ | ↓ | ↓ | ↓ | ↓ | ↔ | |
NFKBIL1 | ↔ | ↔ | ↔ | ↔ | ↓ | ↔ | |
PTGS1 | ↓ | ↓ | ↓ | ↓ | ↔ | ↑ | |
PTGS2 | ↔ | ↑ | ↓ | ↑ | ↑ | ↔ | |
SOCS3 | ↔ | ↔ | ↓ | ↔ | ↑ | ↑ | |
group II | KRT4 | ↓ | ↓ | ↓ | ↓ | ↓ | ↓ |
KRT8 | ↔ | ↑ | ↑ | ↑ | ↓ | ↑ | |
KRT 15 | ↓ | ↓ | ↓ | ↓ | ↓ | ↓ | |
KRT18 | ↔ | ↔ | ↔ | ↔ | ↔ | ↑ | |
group III | FZD5 | ↔ | ↔ | ↔ | ↓ | ↑ | ↔ |
SOX4 | ↔ | ↑ | ↑ | NA | ↓ | ↑ | |
SOX9 | ↔ | ↑ | ↑ | ↑ | ↔ | ↑ | |
SOX15 | ↓ | ↓ | ↓ | ↓ | ↔ | ↑ | |
TMEM2 | ↔ | ↑ | ↑ | ↑ | ↓ | ↑ | |
group IV | TIMP1 | ↔ | ↓ | ↓ | ↔ | ↔ | ↑ |
TNFRSF10B | ↔ | ↓ | ↓ | ↔ | ↓ | ↑ | |
IFNGR1 | ↔ | ↓ | ↔ | ↓ | ↓ | ↔ |
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Korbut, E.; Krukowska, K.; Magierowski, M. Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models. Int. J. Mol. Sci. 2022, 23, 3312. https://doi.org/10.3390/ijms23063312
Korbut E, Krukowska K, Magierowski M. Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models. International Journal of Molecular Sciences. 2022; 23(6):3312. https://doi.org/10.3390/ijms23063312
Chicago/Turabian StyleKorbut, Edyta, Kinga Krukowska, and Marcin Magierowski. 2022. "Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models" International Journal of Molecular Sciences 23, no. 6: 3312. https://doi.org/10.3390/ijms23063312