Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression through A2AR-Akt-β-Catenin Signaling
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Case Selection
2.2. Tissue Microarray and Immunohistochemistry (IHC)
2.3. Evaluation of IHC Data
2.4. Reagents and Cell Lines
2.5. Establishment of RT-R-BC Cells
2.6. Total RNA Extraction and Reverse Transcription Polymerase Chain Reaction (RT-PCR)
2.7. Extracellular ADO and ATP Measurements
2.8. Cell Proliferation Assay
2.9. Gene Silencing by siRNA Transfection
2.10. Colony Formation Assay
2.11. Matrigel Invasion Assay
2.12. Protein Extraction and Western Blot Analysis
2.13. Animal Experiments
2.14. Statistical Analysis
3. Results
3.1. The Expression of A2AR, A2BR, and CD73 Is Increased in TNBC and Further Increased in RT-R-TNBC Cells
3.2. Control- and TNF-α-Treated MDA-MB-231 Cells Show Higher Extracellular ATP and ADO Levels Than Non-TNBC Cells, and This Effect Is Further Enhanced in RT-R-MDA-MB-231 Cells
3.3. The Expression of A2AR, but Not A2BR, CD39, and CD73, Is Significantly Increased in BC Patient Tissues, Especially TNBC Patient Tissues, Compared to Normal Epithelial Tissues
3.4. Extracellular ADO Enhances the Proliferation, Colony Formation, and Invasion of MDA-MB-231 and RT-R-MDA-MB-231 Cells through A2AR Activation
3.5. Extracellular ADO-Mediated Activation of A2AR Stimulates AKT Activation and Induces β-Catenin, Snail, and Vimentin Expression, Which Are Involved in Tumor Invasion and Metastasis
3.6. A2AR Is Involved in the Progression and Metastasis of BC In Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
A2AR | adenosine receptor type 2A |
A2BR | adenosine receptor type 2B |
AC | adenyl cyclase |
ADO | adenosine |
AJCC | American Joint Committee on Cancer |
BC | breast cancer |
CCK-8 | Cell Counting Kit-8 |
CTRL | control |
ECL | enhanced chemiluminescence |
ECs | endothelial cells |
EMT | epithelial–mesenchymal transition |
EV | empty vectors |
HRP | horseradish peroxidase |
IHC | immunohistochemistry |
NK | natural killer |
OD | optical density |
P2Y2R | P2Y purinoceptor 2 |
RT-PCR | reverse transcription polymerase chain reaction |
RT-R | radiotherapy-resistant |
SD | standard deviation |
TMA | tissue microarray |
TME | tumor microenvironment |
TNBC | triple negative breast cancer |
WHO | World Health Organization |
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Characteristics | A2AR | p | A2BR | p | ||
---|---|---|---|---|---|---|
Low (n = 97) | High (n = 83) | Negative (n = 108) | Positive (n = 72) | |||
Age (years) | 51 (30–81) | 51 (25–82) | 0.637 | 51 (30–81) | 51 (25–82) | 0.699 |
Sex | 0.461 | 0.400 | ||||
Female | 97 (100.0) | 82 (99.8) | 108 (100.0) | 71 (98.6) | ||
Menopausal status | 0.651 | >0.990 | ||||
Pre | 44 (45.4) | 34 (41.0) | 47 (43.5) | 31 (43.1) | ||
Post | 53 (54.6) | 48 (57.8) | 61 (56.6) | 40 (55.6) | ||
Histology | 0.055 | 0.785 | ||||
Ductal | 93 (95.9) | 73 (88.0) | 99 (91.7) | 67 (93.1) | ||
Others | 4 (4.1) | 10 (12.0) | 9 (8.3) | 5 (6.9) | ||
ER status | <0.001 | 0.093 | ||||
Negative | 14 (14.4) | 36 (43.4) | 25 (23.1) | 25 (34.7) | ||
Positive | 83 (85.6) | 47 (56.6) | 83 (76.9) | 47 (65.3) | ||
PR status | 0.133 | 0.234 | ||||
Negative | 22 (22.7) | 28 (33.7) | 34 (31.5) | 16 (22.2) | ||
Positive | 75(77.3) | 55 (66.3) | 74 (68.5) | 56 (77.8) | ||
HER-2 status | 0.685 | 0.543 | ||||
Negative | 80 (82.5) | 71 (85.5) | 89 (82.4) | 62 (86.1) | ||
Positive | 17 (17.5) | 12 (14.5) | 19 (17.6) | 10 (13.9) | ||
TNBC | 0.002 | 0.155 | ||||
Yes | 4 (4.1) | 16 (19.3) | 9 (8.3) | 11 (15.3) | ||
No | 93 (95.9) | 67 (80.7) | 99 (91.7) | 61 (84.7) | ||
AJCC 8th stage | 0.135 | 0.916 | ||||
I | 33 (34.0) | 37 (44.6) | 42 (38.9) | 28 (38.9) | ||
II | 47 (48.5) | 28 (33.7) | 46 (42.6) | 29 (40.3) | ||
III | 17 (17.5) | 18 (21.7) | 20 (18.5) | 15 (20.8) | ||
Surgery | 0.532 | 0.341 | ||||
MRM | 32 (33.0) | 32 (38.6) | 35 (32.4) | 29 (40.3) | ||
BCS | 65 (67.0) | 51 (61.4) | 73 (67.6) | 43 (59.7) | ||
Adjuvant chemotherapy | 0.806 | 0.801 | ||||
Yes | 88 (90.7) | 74 (89.2) | 98 (90.7) | 64 (88.9) | ||
No | 9 (9.3) | 9 (10.8) | 10 (9.3) | 8 (11.1) | ||
Adjuvant radiotherapy | 0.608 | 0.119 | ||||
Yes | 74 (76.3) | 60 (72.3) | 85 (78.7) | 49 (68.1) | ||
No | 23 (23.7) | 23 (27.7) | 23 (21.3) | 23 (31.9) | ||
Adjuvant hormone therapy | 0.018 | 0.521 | ||||
Yes | 89 (91.8) | 65 (78.3) | 94 (87.0) | 60 (83.3) | ||
No | 8 (8.2) | 18 (21.7) | 14 (13.0) | 12 (16.7) |
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Share and Cite
Jin, H.; Lee, J.-S.; Kim, D.-C.; Ko, Y.-S.; Lee, G.-W.; Kim, H.-J. Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression through A2AR-Akt-β-Catenin Signaling. Cancers 2021, 13, 2105. https://doi.org/10.3390/cancers13092105
Jin H, Lee J-S, Kim D-C, Ko Y-S, Lee G-W, Kim H-J. Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression through A2AR-Akt-β-Catenin Signaling. Cancers. 2021; 13(9):2105. https://doi.org/10.3390/cancers13092105
Chicago/Turabian StyleJin, Hana, Jong-Sil Lee, Dong-Chul Kim, Young-Shin Ko, Gyeong-Won Lee, and Hye-Jung Kim. 2021. "Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression through A2AR-Akt-β-Catenin Signaling" Cancers 13, no. 9: 2105. https://doi.org/10.3390/cancers13092105